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FEBS Letters, 513
Hindawi Journal of Oncology Volume 2019, Article ID 7079604, 14 pages https://doi.org/10.1155/2019/7079604 Review Article Anne Ackermann and Angela Brieger Medical Clinic I, Biomedical Research Laboratory, University Clinic Frankfurt, Frankfurt am Main, Germany Correspondence should be addressed to Angela Brieger; firstname.lastname@example.org Received 18 March 2019; Revised 5 April 2019; Accepted 9 April 2019; Published 2 May 2019 Academic Editor: Giandomenico Roviello Copyright © 2019 Anne Ackermann and Angela Brieger. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nonerythroid spectrin훼II (SPTAN1) is an important cytoskeletal protein that ensures vital cellular properties including polarity and cell stabilization. In addition, it is involved in cell adhesion, cell-cell contact, and apoptosis. eTh detection of altered expression of SPTAN1 in tumors indicates that SPTAN1 might be involved in the development and progression of cancer. SPTAN1 has been describedincancerandtherapy response andproposedasapotentialmarkerprotein forneoplasia,tumor aggressiveness,and therapeutic efficiency. On one hand, the existing data suggest that overexpression of SPTAN1 in tumor cells reflects neoplastic and tumor promoting activity. On the other hand, nuclear SPTAN1 can have tumor suppressing effects by enabling DNA repair through interaction with DNA repair proteins. Moreover, SPTAN1 cleavage products occur during apoptosis and could serve as markers for the efficacy of cancer therapy. Due to SPTAN1’s multifaceted functions and its role in adhesion and migration, SPTAN1 can influence tumor growth and progression in both positive and negative directions depending on its specific regulation. This review summarizes the current knowledge on SPTAN1 in cancer and depicts several mechanisms by which SPTAN1 could impact tumor development and aggressiveness. 1. Background locus [9–11]. As this heterogeneity occurs at the C-terminus near potential calcium and actin-binding domains, it is Nonerythroid spectrin훼II (SPTAN1, also termed 훼-Fodrin) possible that different isoforms fulfill different functions . is a cytoskeletal protein that belongs to the family of spectrins. Alternatively spliced forms of SPTAN1 were also identified to be unique in different tissues . The spectrin family includes several structural proteins ( 훼- and 훽-spectrin, 훼-actinin, dystrophin, and utrophin) that SPTAN1 is mapped to chromosome 9q33 -> q34, encom- build and stabilize the cytoskeleton by forming a hexagonal passes 7,787 nucleotides, and encodes for a 2,472 amino acid mesh under the plasma membrane and ensuring stability protein with a predicted molecular weight of 284 kDa . eTh and organization of organelles in the cell [1, 2]. Antiparallel protein contains 22 domains, of which domains 1-9 and 11-21 heterodimers of훼-and훽-spectrin form tetramers in a head comprise the spectrin typical triple helical repeats consisting to head arrangement, which allow stabilization of interacting of 106 amino acids (Figure 1). Domain 10 is a src homology partners and serve as a structural platform for various domain 3 (SH3) motif known to be involved in cytoskeletal interactions [4, 7]. Interactions of spectrin repeats are diverse transmembrane proteins including channels, receptors, and transporters [3–6]. and defy any classification of their preferred interaction site In humans, spectrin isoforms are encoded by two 훼- but are crucial wherever they are identiefi d . Due to and ve fi 훽-spectrin genes [4, 7]. 훼-spectrin, exclusively their unique binding properties, spectrin repeats can have expressed in erythroid cells, is termed erythroid spectrin important roles in assembly of complex and multiprotein 훼I (SPTA1), while SPTAN1 represents the ubiquitous form structures involved in cytoskeletal architecture as well as in in all other cell types. Human SPTA1 and SPTAN1 only forming large signal transduction complexes . Domain share 58% sequence identity and differ markedly in their 11 harbors a cleavage site for calpain (also termed calcium- carboxy-terminal sequence [8, 9]. Both can be expressed as activated protease 1, CDP-1) and a calmodulin-binding site different isoforms through alternative splicing from one gene [13, 14]. The C-terminal domain 22 is related to calmodulin 2 Journal of Oncology miRNA-128-3p Calpain cleavage site potential E2/3 activity potential CaM-like Y1176 C residues EF ’ SPTAN1 P 3 UTR N C 121 34 5 6 7 8 9 A 112 13 14 15 16 17 18 19 20 21 22 SH3 20 aa potential MLH1 2+ binding site Ca CaM Cx 43 EVL, TES, FANCG .. .. 3 21 CH Calpain-mediated SPTBN1 proteolysis Actin Domains/spectrin repeat C-/N-terminus EF-hand Figure 1: Structure of SPTAN. SPTAN1 harbors 22 domains, which are presented in green. Shown are the following: characteristic spectrin repeats (green boxes); C- and N-terminus (green rectangle); domain 10 with a SH3 domain (blue circle), which allows binding of EVL, TES, and FANCG; a 20 amino acid (aa) motif and alternatively spliced region between domains 10 and 11, which allows specific binding of Connexin 43 (Cox43); phosphorylation site (orange) at residue Y1176 in domain 11 and behind that the calpain cleavage site of SPTAN1 and the calmodulin (CaM) binding site, which regulates calpain-mediated proteolysis; a potential MLH1 binding site between domains 18 and 22; potential cystein (C) residues (orange lines) in domain 20, which might mediate a potential E2/E3 ubiquitin-protein-conjugating or -ligating activity; domains 20 and 21, which mediate dimerization of SPTAN1 and SPTBN1 by binding to the N-terminal first two spectrin repeats of SPTBN1 (yellow)  and C-terminal the CaM-like domain 22, which can bind calcium through two EF-hand motifs. Translational inhibition by miRNA-128-3p targets the 3 untranslated region (3 UTR) of SPTAN1 . SPTBN1 can bind actin through its N-terminal Calponin homology (CH) domain . Spectrin heterodimers formed by antiparallel lateral dimerization of SPTAN1 and SPTBN1 then form tetramers by head to head assembly [3, 4]. Modified aer ft Bennett and Baines (2001) and Baines (2010) [4, 17]. and can bind calcium through two EF-hand calcium-binding execute various functions. In the nucleus (Figure 3), SPTAN1 motifs [1, 4, 15]. es Th e EF-hand motifs are juxtaposed to was shown to interact with different proteins involved in the actin-binding domain on the adjacent훽-spectrin subunit DNA repair, chromatin remodeling, and fanconi anemia (FA) (Figure 1) . Hence, both calpain and calmodulin might and with transcription factors, indicating that it potentially enhance actin-binding capacities of spectrin. affects various critical cellular pathways [24, 25]. Further Due to their role as scao ff lding proteins, spectrins interact functions have been proposed for spectrins including control with numerous different binding partners and therefore fulfill of cell proliferation, a role in protein sorting and trafficking, multiple functions such as organization of a cytoskeleton control of cell division, and transcription activity, which underlying the plasma membrane and regulation of the activ- remain yet unknown for SPTAN1 but are intriguing avenues ity of transmembrane proteins they interact with. Together to investigate for a broader understanding of this protein with nonerythroid spectrin 훽II (SPTBN1), SPTAN1 can biology . influence the cytoskeleton organization by interacting with In line with the functional diversity of SPTAN1, it is not membrane-associated proteins including ankyrin, protein surprising that SPTAN1 appears to play a role in tumorigene- 4.1, and adducin as well as the actin cytoskeleton [3, 18]. In sis. The hallmarks of cancer include sustaining proliferative addition, SPTAN1 can also modulate different ion channels signaling, evading growth suppressors, activating invasion and other involved proteins [4, 7, 19]. Besides its function and metastasis, inducing angiogenesis, and resisting cell as a cytoskeletal scao ff lding protein (Figure 2(a)), the ubiq- death and meanwhile have been extended to deregulation of uitous expression of SPTAN1 indicates additional important cellular energetics, genome instability, and mutations [26, 27]. functions for this protein, which has been described in eTh refore, proteins involved not only in one but many tumor cell mechanisms including development, cell shape, cell-cell types and in a broad spectrum of cancer characteristics, contact, apoptosis, cell adhesion, and cell cycle [20–23]. Fur- features, and mechanisms are of highest interest, as they thermore, SPTAN1 is not confined to the plasma membrane might serve as potential biomarkers or even as predictors of but can also be distributed throughout the cell where it may therapeutic response. Journal of Oncology 3 Cytoskeletal functions SPTBN1 Calcium SPTAN1 Ca2+ E-cadherin Ankyrin Na/K-ATPase Cell polarity cell cell contact EMT /adhesion Metastasis (a) Calcium Proliferation High level of cytoplasmic SPTAN1 as marker for neoplasia Migration reduced SPTAN1 Actin (b) SPTAN1 alternative splicing Survival and angiogenesis and cleavage 20aa P Cx43 20aa Cx43 Casp gap junctions Calpain Apoptosis CaM P P Degradation of FAK, PXN Casp cell rounding, detachment Calpain Activation of other cellular mechanisms (c) Figure 2: Localization and functional relevance of cytoplasmic SPTAN. SPTAN1 can have diverse functions in the cell depending on its localization. (a) SPTAN1 (green bars) serves as cytoskeletal scao ff ldin g protein and, under physiological calcium levels, together with SPTBN1 (yellow bars) and other proteins, it forms a stabilizing mesh beneath the cell membrane allowing cell polarity. Shown are epithelial cells expressing SPTAN1 apically and laterally in the cell. Upon cell-cell contact (orange bars), SPTAN1 interacts with E-cadherin, ankyrin, and Na/K-ATPase and thus might influence EMT and metastasis. (b) SPTAN1 can aec ff t tumor growth and outcome by enhancing cell proliferation and migration (upper panel), which are impaired in case of reduced SPTAN1 levels (lower panel). High levels of cytoplasmic SPTAN1 in proliferating cells could be used as marker for neoplasia. Moreover, migration might be influenced by the interaction of SPTAN1 and SPTBN1 with actin filaments. (c) SPTAN1 has also a role in survival, angiogenesis, apoptosis, and other cellular mechanisms through expression of alternative spliced forms and cleavage products. A SPTAN1 spliceform including a 20 amino acid (aa) motif contributes to gap junctions (orange dumbbells) through association of this motif with Connexin 43 (Cx43). This association is regulated by JNK-mediated phosphorylation. Expression of this spliceform is repressed during hypoxia, thus leading to a decrease in gap junctions. SPTAN1 is involved in apoptosis if cleaved by calpain and caspases. This is regulated by phosphorylation of Y1176 and dephosphorylation enhances the proteolytic susceptibility of SPTAN1 to calpain and caspases 2, 3, and 7. Cleavage leads to membrane blebbing and irreversible cell death. Caspase- mediated cleavage can be inhibited by calmodulin (CaM) binding and indicates again the influence of calcium homeostasis. SPTAN1 cleavage products can further lead to cell rounding and detachment by degrading FAK and paxillin (PXN) and can activate further yet unknown cellular mechanisms. 4 Journal of Oncology FA complex TRF XPF PMS2 MLH1 A G XPF Nucleus SPTAN1 DNA damage (ICLs) DNA mismatch Figure 3: SPTAN in DNA repair. SPTAN1 can translocate into the nucleus. In the nucleus, SPTAN1 can interact with various partners including proteins involved in DNA repair and fanconi anemia (FA). By binding FA proteins in nuclear complexes, SPTAN1 is stabilized and might act as scaffold to align or enhance DNA repair associated proteins at sites of damage. eTh FA protein FANCG (G) is able to bind to SPTAN1 through its SH3 domain. Via FANCA (A) and XPF, SPTAN1 enables DNA repair of interstrand crosslinks (ICLs). SPTAN1 circumvents telomere dysfunction aer ft ICL damage by interaction with TRF1/2 and XPF. Furthermore, SPTAN1 can directly interact with MLH1, which mediates DNA mismatch repair (MMR). FANCJ, which is required for correction of the cross-link response, also interacts with the MMR complex MutL훼, consisting of MLH1 and PMS2. A SPTAN1-dependent DNA repair mechanism, however, still remains unknown. Due to the wide range of SPTAN1’s actions, it can SPTAN1 was detectable not only in colon adenomas and car- potentially inu fl ence several or even every step from tumor cinomas but also in Crohn’s disease and tumor environment development to progression and metastasis. Therefore, it is and other epithelial neoplasms including adenocarcinomas vital to better understand its involvement in various functions of breast, stomach, and small intestine, suggesting enhanced and mechanisms affecting cancer. SPTAN1 level as a nonspecicfi marker for neoplasia of both By combining the current knowledge of SPTAN1 in can- benign and malignant origin . A model established for cer and illustrating potential mechanisms for SPTAN1 influ- SPTAN1 in cancer assumed increased apical SPTAN1 as a ence on tumor development, progression, patient outcome, reaction to pathological stress at the brush border, whereas and therapeutic response, this review aims to summarize increased cytoplasmic levels marked neoplastic activity . existing data about the role of SPTAN1 in carcinogenesis. Whether rearrangements in SPTAN1 localization are depen- However, there are still many unanswered questions and dent on actin filaments and whether SPTAN1 exists on further investigations are mandatory to better understand membranes or in the cytoplasm with or without SPTBN1 the role of SPTAN1 as a potential neoplasia, tumor, and remain under speculation. Additionally, the predictive value therapeutic response marker. of SPTAN1 expression to distinguish neoplastic tissue in samples and biopsies is still under discussion. In 2013, a proteogenomic analysis of human CRC 2. SPTAN1 in Various Cancer Types cell lines representing different pathological stages identi- Until now, changes in the expression of SPTAN1 have been fied SPTAN1 and SPTBN1 as potential markers for tumor described in a variety of tumors and tissues but defy any clear and metastases state . Whereas SPTBN1 was reduced, classification. SPTAN1 rather seems to have opposite effects in SPTAN1 expression was increased in moderately invasive and different tumors. On one hand, the majority of data suggest poorly differentiated CRC compared to nonpolyposis cancer overexpression of SPTAN1 in cancer and progression. On cell lines . the other hand, reduced expression of SPTAN1 has also been By comparing SPTAN1 expression level in DNA mis- observed in tumors. match repair- (MMR-) deficient and MMR-proficient col- In light of a decrease in SPTAN1 expression, we observed orectal cancer or other cell lines, our group could demon- in MLH1-deficient tumors and similar to data recently strate that loss of the MMR protein MLH1 was correlated described for the membrane-associated skeletal protein with a significant reduction of SPTAN1 expression . adducin , we propose that SPTAN1 might function two- Since previously performed two hybrid experiments showed sided as a tumor suppressor or promotor. Studies that have interaction of SPTAN1 with MLH1, the connection between investigated expression and mechanisms of action of SPTAN1 loss of MLH1 and SPTAN1 reduction might be explained by in tumors have allowed gaining some insights into its role in lack of interaction and therefore destabilization of SPTAN1 in cancer.TheyaresummarizedinTable 1. absence of MLH1 in MLH1-deficient cell lines . Very recently our group analyzed the connection between .. SPTAN in Colorectal Cancer. Overexpression of SPTAN1 SPTAN1 andMLH1inalargecohortofCRCsand we in cancer was first described in 1989 in sporadic colorectal observed clearly enhanced SPTAN1 level in sporadic CRCs cancer (CRC) by Younes et al. and has been reported to pro- compared to normal adjacent mucosa, while MLH1-deficient mote tumorigenesis . Interestingly, increased cytoplasmic sporadic CRCs or Lynch syndrome tumors showed a visible Journal of Oncology 5 Table 1: SPTAN1 in various cancer types. Tumor Type Changes in SPTAN1 References SPTAN1 upregulation  SPTAN1 downregulation in MLH1-deficient CRC  Colorectal cancer (CRC) SPTAN1 upregulation in sporadic CRC, SPTAN1 downregulation in  MLH1-deficient CRC Gastric cancer SPTAN1 upregulation [28, 31, 32] SPTAN1 upregulation  Lung cancer SPTAN1 mutations and downregulation  Breast cancer SPTAN1 upregulation (cytoplasmic) [28, 35, 36] Bladder cancer Recurrence-associated SPTAN1 alterations  SPTAN1 downregulation in lung metastasis, SPTAN1 as progression Prostate cancer  gene Cutaneous tumors SPTAN1 upregulation (cytoplasmic)  Soft-tissue tumors SPTAN1 upregulation in more aggressive mesenchymal tumors  Ovarian cancer SPTAN1 upregulation aer ft chemotherapy  Atypical chronic myeloid leukaemia Novel CSF3R-SPTAN1 fusion gene  (aCML) Non-Hodgkin lymphoma SPTAN1 as target protein in postchemotherapy  Non-Hodgkin lymphoma, acute SPTAN1 upregulation after chemotherapy in nuclear area  lymphoblastic leukaemia (ALL) reduction in SPTAN1 expression . In addition, we could intense staining and expression of SPTAN1 in all types of lung demonstrate that downregulation of SPTAN1 expression via carcinomas compared to normal tissue . Strong intra- shRNA resulted in reduced cell-cell contact, impaired cell cytoplasmic and membrane-associated staining in tumors proliferation, and decreased migration in vitro . eTh was observed not only for SPTAN1 but also for the mul- observed association of MLH1 status with SPTAN1 expression tifunctional, filamentous protein actin. eTh y suggested that in CRC suggests a predictive value for SPTAN1 as a marker for the diffuse distribution of SPTAN1 features undifferentiated cancer development and progression. reserve cells and reflects a high proliferative capacity. In clinical practice, MMR-deficient tumors show better Twenty years later, SPTAN1 again became a gene of clinical outcome and less metastasis than tumors with func- interest in lung cancer when it was identified by exome and tional MMR . eTh exact reasons for this divergent behav- mRNA sequencing in lung adenocarcinoma . eTh data ior are still unclear, but SPTAN1 might play an important role, showed that in never-smokers SPTAN1 harbors recurrent as reduced SPTAN1 levels have been shown to significantly mutations and correlates with pathway deregulation and impair proliferation and migration in different CRC cell lines worse clinical outcome . However, in this case, SPTAN1 . Interestingly, when patient outcome and metastasis were was reduced in tumors compared to normal lungs and could correlated with SPTAN1 expression, a decline in SPTAN1 indicate impaired DNA repair . Whether this is due to levels was found with increasing tumor stage and metastatic the identified mutations in SPTAN1 still remains unclear. status, which accentuates the divergent role of SPTAN1 . Interestingly, in vitro data of lung cancer cells demonstrated that SPTAN1 is suppressed by microRNA-128-3p, which led to enhanced sensitivity to cytostatic mitomycin C (MMC) by .. SPTAN in Gastric Cancer. Until now, only two studies limiting DNA repair capacity . have described SPTAN1 expression in gastric cancer [31, 32]. In the rfi st study, published in 2002, Lee and coworkers identified SPTAN1 as a differentially expressed gene in gastric .. SPTAN in Leukemia. In leukemia cell lines, enhanced cancer using cDNA microarrays . Since the data showed expression of heterodimeric SPTAN1/SPTBN1 was shown that SPTAN1 was enhanced in the intestinal type of gastric to be induced by dimethyl sulfoxide (DMSO) treatment cancer, Lee et al. suggested SPTAN1 as a marker for classifying followed by local rearrangement of this protein complex gastric cancers. This was confirmed two years later by Zhang . In contrast, Hashida et al. only saw a slight increase in et al. showing that SPTAN1 gene expression was significantly SPTAN1/SPTBN1 but major changes in actin during myeloid higher in gastric cancer tissue as well as dysplastic tissue than leukemia cell differentiation and therefore concluded that in normal mucosa . this heterodimer did not have a major function in actin- induced cell motility . However, alternative pathways .. SPTAN in Lung Cancer. In lung cancer, SPTAN1 was of SPTAN1 function besides actin-mediated cell structuring first described in 1994 by Sormunen et al. who found more seem increasingly likely. 6 Journal of Oncology In 2017, the first SPTAN1 fusion gene was described in an potential of SFTs could be shown. This might be due to atypical chronic myeloid leukemia (aCML) patient . At a different metastatic pattern of sarcomas compared to the RNA level, C-terminal SPTAN1 including an incomplete carcinomas, which metastasize rather to the lung and liver spectrin repeat and the EF-hand domain was fused to colony- than to lymph nodes, and missing information on the role stimulating factor 3 receptor (CSF3R), which is frequently of SPTAN1 in this regard . mutatedinaCML.Theaeff cted patientshowedpoorresponse to src kinase inhibitor therapy with Dasatinib, suggesting 3. SPTAN1 in Cancer Development that the fusion transcript could not be sucffi iently inhibited and Progression and instead kept activating distinct signaling pathways . Binding of calcium via the EF-hand domain of SPTAN1 As described in detail above, a change of SPTAN1 expression and a resulting conformational and functional change could level has been found in various tumor entities. In particular, contribute to this activity. However, this hypothesis needs SPTAN1 seems to have an important impact on cancer further claricfi ation. development and progression by various mechanisms. In 2000, Gascard and Mohandas  suggested the idea .. SPTAN in Other Cancer Types. Regarding the expres- of cytoskeletal proteins including spectrin as key players in sion of SPTAN1 in other tumor entities, little has been signal transduction pathways, by anchoring or regulating publishedsofar. kinases and their corresponding proteins . SPTA1 was In breast cancer, altered expression and upregulation of demonstrated to interact with protein kinase C and tyrosine membranous and cytoplasmic SPTAN1 were observed in two kinase [51, 52]. In addition, SPTAN1 has been shown to independent studies, in 1992 and 1999 [35, 36]. In particular interact via its SH3 domain with phosphoproteins participat- high-grade tumors showed cytoplasmic accumulation of ing in actin assembly, including Ena/vasodilator-stimulated SPTAN1, which positively correlated with p53 expression phosphoprotein-like protein (EVL)  and vasodilator- . stimulated phosphoprotein (VASP) which induces apoptosis In bladder cancer, SPTAN1 was identified in recurrence- by SPTAN1 breakdown depending on the VASP phosphory- associated gene signatures and suggested as a predictor of lation status(Figure1)[54,55].Theobservedinteraction of disease recurrence at an early tumor stage . Significant SPTAN1 with EVL and the potential tumor suppressor Tes changes in SPTAN1 were observed in the group of patients tfi swellinthisfunctionalcontextandmightfurthermore without recurrence . influence cell-cell contacts and focal adhesions [3, 56]. Until now, no data regarding the expression level of SPTAN1 in prostate carcinomas are available. However, reduced SPTAN1 expression was found in a lung metastasis .. SPTAN as a Tumor Promoter. As already mentioned, of a prostate cancer patient . In this study, SPTAN1 was SPTAN1 has been mostly shown to be upregulated in tumors identified as a suitable candidate for the prediction of prostate compared to normal mucosa (Table 1) [28, 32, 33, 35, 36, tumor progression and suggested as a potential biomarker 39–41]. In particular, SPTAN1 expression was increased . heterogeneously in the cytoplasm, whereas membrane bound In cutaneous tumors of various origins, loss of SPTAN1 partly disappeared as described in cutaneous tumors membrane-associated SPTAN1 was detected, whereas . This localization change is probably due to a switch of cytoplasmic staining of SPTAN1 was increased and associated SPTAN1's function. with less differentiated, invasive cells of these tumors . Whereas membranous SPTAN1 can act as a cytoskeletal Basal as well as squamous cell carcinomas and malignant scao ff ld by interacting with associated proteins and thereby melanomas display increasing invasion and metastatic ensures cell polarity, its distribution throughout the cell capacities, probably reflected by the different patterns of allows SPTAN1 access to other potential interacting partners SPTAN1 expression. This supports the concept that the andmay enhancecellgrowthandcell proliferation. absence or decrease of membrane-associated SPTAN1 eTh refore, increase of cytoplasmic SPTAN1 was related to is essential for proliferation and increased cytoplasmic the proliferative and invasive capacity of cells and sug- SPTAN1 during invasion . In melanomas, however, some gested as a marker for neoplasia (Figure 2(b)) [28, 36, 39, cells were strongly stained, while others were completely 57,58].TheimpactofSPTAN1onproliferation couldbe negative for SPTAN1. eTh refore, the expression of SPTAN1 confirmed by in vitro data of our group showing a clear in melanomas must be clarified by further investigation. decrease of cell proliferation in SPTAN1-deficient cells . Looking at soft tissue tumors (SFTs), increasing SPTAN1 The exact molecular mechanism, however, is yet unclear. level and more aggressive tumor behavior were also described Loss of membranous SPTAN1 leads to loss of cell polarity, . eTh expression of SPTAN1, identified by gene expression which is the prerequisite for depolarization and proliferation profiling, was higher in more aggressive types of desmoid- and might therefore induce cell growth . In this case, type fibromatosis and malignant mesenchymal tumors com- various SPTAN1-containing membrane complexes including pared to benign mesenchymal tumors. eTh study suggests spectrin-actin crosslinks and the SPTAN1-ankyrin-protein SPTAN1asamarkerand/ortargetinSFTsfunctionallyrelated 4.1-adducin complexes might be aeff cted, leading to alter- to locally aggressive tumors. Curiously, elevated SPTAN1 ation in membrane trafficking, cell signaling, and adhesion expression could not be confirmed at the RNA and protein complexes and to mechanically fragile cell membranes [17, level and no association of SPTAN1 with the metastatic 18, 59, 60]. Furthermore, cytoplasmic SPTAN1 could interact Journal of Oncology 7 with different partners and undergo distinct posttranslational . A gradual assembly of ankyrin-spectrin based matrix modifications. Phosphorylation of SPTAN1 at tyrosine Y1176 at sites of E-cadherin-induced cell-cell-contact may also might, for example, activate cellular mechanisms that allow involve recruitment of ankyrin-spectrin-complexes linked to or promote SPTAN1 breakdown (Figure 1) . Besides other integral membrane proteins including Na/K-ATPase increased cytoplasmic localization, a second pathological . These processes are of high interest for epithelial- change for SPTAN1 has been described: increased abundance mesenchymal transition (EMT). In EMT, which is an impor- of SPTAN1 especially in the apical regions of epithelial cells, tant feature in cancer initiation and metastasis by enabling which might lead to enhanced extension of core actin bundles migration, calcium-dependent cadherins like E-cadherin are into the cytoplasm and a thickened web . Otherwise, involved. In order to understand if SPTAN1 is essential for SPTAN1 could be located in more central cytoplasmic regions cytoskeletal integrity it would be interesting to analyze, on by actin bundles. This may promote cell growth as well but one hand, whether the loss of SPTAN1 aeff cts the cytoskele- also enables transport of SPTAN1 and other interacting pro- tal interacting proteins including actin, ankyrin, adducin, teins into the cytoplasm, where it might act as a “switchboard” protein 4.1, and calmodulin. On the other hand, interacting . proteins like E-cadherin involved in EMT processes are of How the enhanced cytoplasmic SPTAN1 level is managed high interest. by the cell is still not clear. In erythroleukemic cells, SPTAN1 During tumor growth and development, cell survival has been shown to be induced by treatment with DMSO under low oxygen conditions and angiogenesis become more followed by rearrangements into submembranous patches and more important. Interestingly, hypoxia-induced splicing and caps . DMSO was also described to induce cardiac of SPTAN1 has been described in endothelial cells, suggesting differentiation in P19 embryonal carcinoma stem cells; how- a role in angiogenesis-mediated cytoskeletal remodeling . ever, this mechanism also remains unresolved . Another Thisisprobablyfacilitated byalongerSPTAN1isoform mechanism influencing the localization of SPTAN1 might harboring 20 additional amino acids (aa) C-terminal to the be based on the cellular ionic environment. Depending on SH3 domain, which is specifically localized at gap junctions calciumlevels,SPTAN1hasbeenshowntochangeitslocaliza- and associates with connexin 43 (Cx43) (Figures 1 and 2(c)) tion in keratinocytes . Under standard levels of calcium, [70, 71]. This binding is dependent on the 20 aa insertion SPTAN1 was concentrated along the cell margin, whereas a which may be sensitive for phosphorylation by the c-Jun N- low calcium level led to SPTAN1 dissemination throughout terminal kinase (JNK) and thus regulated by JNK signaling the cell and most interestingly a more rapid proliferation [70, 71]. Under hypoxia, generation of this spliceform is of cells . Therefore, SPTAN1 might be able to influence repressed, resulting in expression of a shorter isoform lacking cellular proliferation by calmodulin or calcium binding. This the specicfi 20 aa insertion, and therefore reduced gap speculationisconrfi medbyPerrinetal.whodemonstrated junction formation. Hence, Weigand et al.  suggested that that calcium-induced cell depolarization seems to be the alternative splicing of SPTAN1 contributes to cell survival and calmodulin-dependent stimulus initiating patch formation angiogenesis. by SPTAN1 in secretory cells . SPTAN1 associated with As already mentioned above, breakdown products of membrane-bound actin filaments was also shown to be SPTAN1 were found during apoptosis [23, 55]. Redistribution 2+ hydrolyzed by a Ca -dependent protease during platelet and polar aggregation of SPTAN1 together with PKC휃 is activation, a mechanism leading to cell congregation and an early event of apoptosis and has been suggested as a adhesion . Furthermore, the SPTAN1 interacting protein tool to monitor cell death efficiency . In addition, the calmodulin binds calcium and can have regulatory functions proteolysis of SPTAN1 during apoptosis has been shown to be of cytoskeletal integrity by activating other proteins including dependent on the protooncogene c-myc . SPTAN1 can be calcium-dependent proteases accelerating degradation of cleaved by calpain leading to a 150 kDa fragment . This SPTAN1 . Also sodium/potassium homeostasis could might be regulated by (de)phosphorylation of the residue have influences on SPTAN1, as Na/K-ATPase and cytoskeletal Y1176nearthecalpaincleavagesitebytyrosinekinasesrc proteins including SPTAN1 and ankyrin are accumulated at or the low-molecular-weight phosphotyrosine phosphatase A regions of cell-cell contact [66, 67]. [61, 75]. In prostate cancer cells, SPTAN1 cleaved by calpain Furthermore, enhanced SPTAN1 expression has been induced apoptosis upon treatment with the anticancer drug shown to be associated with invasiveness and more aggres- bicalutamide . However, the cleavage of SPTAN1 by sivetumors [28,36,40].Inthiscontext,SPTAN1seems calpain does not necessarily lead to cell death but rather to also influence cell mobility and invasion. Our group has regulatory functions in secretion and activation under demonstrated SPTAN1-dependent cell migration in CRC physiological conditions . SPTAN1 breakdown products cells which confirms this finding [29, 30]. Similar to cell were also shown to promote adhesion focal disruption, cell surface proteins of nonneuronal cells, SPTAN1 was described rounding, and detachment in epithelial cells . Moreover, to be involved in crosslinking as well as the cap formation dephosphorylation of Y1176 could enhance the proteolytic process . As cap formation is a characteristic of moving susceptibility of SPTAN1 to apoptosis associated caspases cells, SPTAN1 could strengthen cell motility via actin-based including caspases 2, 3, and 7 and cleavage leading to cell motility or via an actin-independent mechanism . Upon shrinkage, membrane blebbing, and irreversible cell death cell-cell contact, SPTAN1 interacts with ankyrin and the (Figure 1) [55, 78, 79]. This is in turn inhibited by calmodulin cell adhesion molecule E-cadherin located on membranes binding and indicates a high influence of calcium home- and brush borders where it might facilitate cell adhesion ostasis . By an independent mechanism through a yet 8 Journal of Oncology unknown caspase, TGF훽 is also able to induce SPTAN1 FA cells . However, FA cell lines exhibit only reduced cleavage and apoptosis . SPTAN1 protein levels, whereas mRNA expression remains Altogether, SPTAN1 is involved in apoptosis through unchanged, suggesting a regulation at the protein level by cleavage by calpain and caspases. It is conceivable that stabilization or degradation . In the nucleus (Figure 3), SPTAN1 bypasses degradation and thus enables tumor SPTAN1 is stabilized through binding to FA proteins in cells to evade apoptosis due to overexpression and altered nuclear complexes and was suggested to act as a scao ff ld to localization of SPTAN1 or altered binding properties to alignorenhanceDNArepairassociatedproteinsatsites of interacting proteins. In ovarian cancer cells, inhibition of damage [25, 89, 90]. One of these FA proteins, FANCG, was SPTAN1 cleavage and apoptosis has been described via an described to bind SPTAN1 by its SH3 domain, which seems alternatively spliced caspase 2 short isoform (casp-2s) . to be necessary for binding also in FA proteins (Figure 1) . Casp-2s inhibits DNA-damage induced cytoplasmic SPTAN1 This role for SPTAN1 is further strengthened by the finding cleavage independent of p53 status and prevents cisplatin- of nuclear SPTAN1 enabling DNA repair of interstrand induced membrane-blebbing. Via this pathway, tumors may crosslinks (ICL) via FANCA and XPF . Furthermore, not only obviate apoptosis but also evade chemotherapy, as SPTAN1 circumvents telomere dysfunction aer ft ICL damage described later. by a related mechanism and interaction with TRF1/2 and XPF Cell rounding and detachment are important first steps . in metastasis. Interestingly, cleavage of SPTAN1 by the As already mentioned, we have also shown that SPTAN1 enteropathogenic E.coli gene EspC leads to sequential degra- is reduced in tumors and cell lines deficient in the MMR dation of the focal adhesion proteins paxillin (PXN) and focal protein MLH1 [29, 30]. Accordingly, our group has previously adhesion kinase (FAK) and consequently to cell rounding demonstrated a direct interaction of SPTAN1 and MLH1 in and detachment . By mechanical coupling of the actin the nucleus . In sporadic MLH1-deficient CRC and in cytoskeleton to a substrate via focal adhesions, cells are MLH1-deficient hereditary Lynch syndrome, SPTAN1 was anchored to the extracellular matrix. By disrupting this mech- shown to be reduced as well, which in addition aeff cted anism, SPTAN1 could have influences on cell detachment, cell viability, mobility, and migration in vitro [29, 30]. Of apoptosis, and migration of cancer cells as described for PXN note, FANCJ also interacts with the MMR complex MutL훼 andFAK,bothofwhich arealsodescribedto be upregulated consisting of MLH1 and PMS2 by binding directly to MLH1 in several cancers [82, 83]. through a helicase domain, and this interaction is required Interestingly, SPTAN1 was mapped near the translocation for correction of the cross-link response . As Peng et breakpoint region on chromosome 9 in the Abelson murine al. suggested, this functional connection of FA and MMR leukemia (ABL) protooncogene which is involved in the predicts a broader role in damage signaling independent of formation of the Philadelphia chromosome in leukemia [84– BRCA1 and might represent a so far unknown repair mech- 86]. Since it was mapped centromeric to the breakpoint, anism involving SPTAN1, MLH1, and FA proteins . Until it is not translocated to chromosome 22 in the human now, SPTAN1-dependent DNA repair signaling pathways are chronic myelogenous leukemia cell line K562 . However, not known in detail. To further elucidate how SPTAN1 is mutations or fusions including SPTAN1 might also aeff ct translocated to the nucleus, which isoforms are involved, and ABL and multilayered downstream signaling. Moreover, which specific functions SPTAN1 has in the nucleus, in DNA SPTAN1 is involved in the regulation of cell-cell contact in repair and potential other mechanisms including chromatin immunological synapse formation in T cells, pointing also to remodeling, a lot of work still has to be done . potential immunological effects . Furthermore, the tumor suppressing properties of SPTAN1 might be regulated throughout the cell and at .. SPTAN as a Tumor Suppressor. Until now, downregu- plasma membranes. In noninvasive squamous carcinoma lation of SPTAN1 was described only in lung cancer, in a cells, SPTAN1 was detected in podosomes, whereas it lung metastasis of prostate cancer, and in MMR-deficient was absent in invasive invadopodia, suggesting a tumor CRC [29, 34, 38]. Suppression of SPTAN1 expression could preventing role . In addition, members of the spectrin- be executed by microRNA-128-3p as shown in lung cancer ankyrin-adducin membrane skeleton were implicated as cells . Interestingly, targeting of SPTAN1 led to reduced tumor suppressors . Protein 4.1R was described to suppress meningioma pathogenesis and 4.1B has growth protein levels, induction of cell cycle arrest, chromosomal instability, and limited DNA repair . Therefore, physiolog- suppressing properties in lung cancer and meningioma as ical SPTAN1 recapitulates several tumor-suppressing charac- well [98–100]. Furthermore, SPTAN1 was shown to interact with Rho GTPase-activating protein and tumor suppressor teristics, whereas alteration in regulation and localization can lead to differential tumor promoting effects. Deleted in liver cancer 1 . Hence, SPTAN1 itself could A role for SPTAN1 as a tumor suppressor is indicated by not only act as a tumor suppressor in the nucleus but also the decline of SPTAN1 in tumor-prone FA patients and in throughout the cell cytoplasm and furthermore stabilize MMR-deficient CRCs [29, 88]. FA is a genetic disorder with other tumor suppressors as described above. Besides the downregulation of SPTAN1 in lung cancer impaired DNA repair function, bone marrow failure, and an increased risk to develop cancer. Interestingly, SPTAN1 compared to normal tissue, Sun et al. described conserved is lacking in cells from FA patients [89–91] and knockdown recurrent gene mutations in both the SPTAN1 gene and mRNA, which were highly correlated with pathway deregula- of SPTAN1 leads to chromosomal instability and impaired interstrand cross-link repair, an eeff ct also observed in tion and worse survival . eTh reduced SPTAN1 expression Journal of Oncology 9 may account for its compromised DNA repair capacity and 4. SPTAN1 in Therapy Outcome other tumor promoting properties. Sun and coworkers could and Chemoresistance not nd fi differences in SPTAN1 expression by comparing SPTAN1 seems to play a role in therapy outcome and tumor with and without mutations . However, it is chemoresistance as well. This is illustrated by a gene expres- unclear whether these mutations cause a change in the sion study of ovarian tumors obtained before and after expression of different isoforms or aeff ct protein stability adjuvant chemotherapy (CT) by L’Esperance et al. . Here, by posttranslational modifications, as this was not analyzed SPTAN1 levels were increased in post-CT ovarian cancer and in the study. A gene mutation may not necessarily cause SPTAN1 was classified as a tumorigenic gene . a change in the expression level but can lead to abnormal In an elegant systems medicine approach, carried out interactions with other proteins and therefore influence by Ajorlooetal.,autoantibodyprofilingwas employed associated pathways or networks . Enriched pathways to identify target proteins aeff cting treatment outcome in for SPTAN1 from exome sequencing included Sertoli cell patients with non-Hodgkin lymphoma . This study iden- junction signaling (SPTA1 was identified here as well) and tified SPTAN1 amongst others as a hub in patients who apoptosis signaling . In addition, mutated SPTAN1 was underwent chemotherapy and as a key protein for therapy mapped in a closely related interaction network of “Cancer, outcome . Indeed, SPTAN1 could be linked to chemore- gastrointestinal disease and respiratory disease” including sistance and different reactome pathways including VEGFR2 caspase, FAK, JNK, and TP53 and suggesting mutual influ- mediated cell proliferation, Erbb2, and PDGF signaling. ence . Changes in spectrin organization were also described earlier Recurrent mutations identified in SPTAN1 were sin- in lymphoid (non-Hodgkin lymphoma) and leukemic (acute gle nonsynonymous nucleotide mutations, namely, C㨀→ T lymphoblastic leukemia) cells upon chemotherapy . alterations in exons 30 and 31 and G㨀→ C substitutions in Here, membrane-associated spectrin remained unchanged, exons 37 to 39 . Mutations and deletions in SPTAN1 whereas increased SPTAN1 appeared as a dense spectrin have been described earlier in disease including intellectual network mainly in the area of the nucleus . How- disability, early-onset dystonia, and epileptic encephalopathy ever, chemotherapeutical response of cisplatin-treated triple- as well as multisystemic vascular dysplasia [102–108]. It was negative breast cancer (TNBC) cells was detected to be suggested that especially in-frame mutations of SPTAN1 may associated with SPTAN1 cleavage . eTh data suggest that exert a dominant-negative eeff ct by inducing aggregation cisplatin-dependent activation of calpain 1 in TNBC cells of defective spectrin subunits and heterotetramers causing induces an increase of calcium and calmodulin by endoplas- instability of various proteins and of the transport machinery mic reticulum stress, whereupon SPTAN1 and caspase 12 are [103, 106, 108]. As the last two spectrin repeats are required for cleaved, which then leads to apoptosis . One therefore heterodimer formation, mutations in this C-terminal region might assume that TNBC cells’ resistance to cisplatin might ofSPTAN1 arecriticalandmighthavemajor consequences. be caused by the lack of calpain 1 activation and the lack In addition, Gartner et al.  suggested that deleterious of spectrin cleavage. Hypothetically, one might also suppose variants of SPTAN1 may cause reduced mRNA expression as that the induction of SPTAN1 cleavage by drugs might be observed in two unique SPTAN1 variants. a promising approach to sensitize cisplatin-resistant TNBC cells. u Th s, SPTAN1 or its cleavage products might also be useful as markers of apoptotic tissue and might give hints on .. Potential E/E Enzymatic Activity of SPTAN. Post- therapeutic efficacy. translational ubiquitination depending on the type and num- The anticancer drug bicalutamide, clinically used in ber of ubiquitin bonds can regulate the half-life and function prostate cancer patients, has been shown to enhance SPTAN1- of proteins as well as their localization within the cell. mediated apoptosis by calpain or caspase 3 leading to cell Ubiquitin-protein-ligases catalyze the transfer of ubiquitin shrinkage and membrane blebbing . SPTAN1-mediated to a protein. Highly interesting in connection with the apoptosis by anticancer drugs has been also described in lung regulation of SPTAN1 function is the discovery of an E2/E3 and hepatocellular carcinoma cells [76, 113]. This therapeutic ubiquitin-protein-conjugating/ligating activity that allows approachmightbeofspecial interestforSPTAN1overex- self-ubiquitination in erythrocyte spectrins [109–111]. Good- pressing cancers, as SPTAN1 degradation is involved in the man et al. suggested also an E2/E3 activity for nonerythroid canonical pathway and might foster tumor cell death. spectrins including SPTAN1 due to sequence homology and Interestingly, theSPTAN1interaction partnerMLH1has conservation of specific cysteines in the spectrin C-terminal been also showntoenhance sensitivitytocisplatin by acti- repeat 20 (Figure 1) . As SPTAN1 is expressed throughout vating apoptosis via a MLH1/ABL signaling pathway . development, found in various cell compartments, associated Besides PARP, caspases 3 and 9 are involved in this pathway with various cytoskeletal components as well as cell adhesion  and suggest a yet unknown role for SPTAN1 in drug proteins and can target by indirect interaction a multitude sensitivity. of other proteins including transporters and channels, the SPTAN1 suppression by microRNA-128-3p led to enzymatic ability of ubiquitination might have a broad impact enhanced sensitivity to cytostatic MMC by limiting DNA on the cell and therefore is intriguing to explore . repair in lung cancer cells which could be applied for Depending on the type and extent of ubiquitination, SPTAN1 adjuvant chemotherapy in lung cancer . However, couldbepreciselyregulatedandwouldbeself-regulating microRNA-128-3p might represent a double-edged sword, as according to its location, function, and degradation. 10 Journal of Oncology it was identified as a novel oncogenic miRNA targeting the Abbreviations tumor suppressor PHF6 gene in T-cell acute lymphoblastic Aa: Amino acid leukemia . Hence, in order to enhance the cytotoxic ABL: Abelson murine leukemia effects of MMC treatment, it might be reasonable to target aCML: Atypical chronic myeloid leukemia SPTAN1 in cancer directly. However, this requires further CaM: Calmodulin claricfi ation and analysis of the mode of action and involved Casp-2s: Caspase 2 short isoform partners. CDP-1: Calcium-activated protease 1, calpain Currently, new approaches to target CRC stem cells are CRC: Colorectal cancer under investigation to improve treatment of severe CRCs, CSF3R: Colony-stimulating factor 3 receptor as recently reviewed by Thenappan et al. . Interestingly, CT: Chemotherapy Wnt and transforming growth factor-훽 (TGF-훽)signaling Cx43: Connexin 43 pathways were described to regulate stem cell function and DMSO: Dimethyl sulfoxide influence cancer , both of which can be potentially ELF: Embryonic liver fodrin influenced by spectrins. SPTBN1, also termed embryonic EMT: Epithelial-mesenchymal transition liver fodrin (ELF), can activate and modulate TGF-훽 by EVL: Ena/vasodilator-stimulated phosphoprotein-like protein Smad activation as found in an SPTBN1-deficient mouse FA: Fanconi anemia model . Furthermore, SPTBN1 expression is reduced in FAK: Focal adhesion kinase early stage CRC and that of Smad4 in advanced carcino- JNK: c-Jun N-terminal kinase mas, which indicates a key role for SPTBN1/Smad4/TGF- MMC: Mitomycin C 훽 signaling in the suppression of cancer progression . MMR: DNA mismatch repair eTh refore, association of SPTBN1 with SPTAN1 is con- PXN: Paxillin ceivable, as different SPTBN1 and SPTAN1 levels could SFT: Soft tissue tumor mutually influence each other. Finally, SPTAN1 could also SH3: Src homology domain 3 influence Wnt signaling by interacting with E-cadherin in SPTA1: Erythroid spectrin훼I an E-cadherin/ankyrin/SPTAN1 complex and thus mod- SPTAN1: Nonerythroid spectrin훼II ulate 훽-Catenin/Wnt but also other signaling pathways SPTBN1: Nonerythroid spectrin훽II . TNBC: Triple-negative breast cancer TGF: Transforming growth factor 5. Conclusions VASP: Vasodilator-stimulated phosphoprotein Y: Tyrosine. SPTAN1 plays an important role in cancer development and progression. The expression level of SPTAN1 is enhanced in several tumors, while it is decreased in others, and Disclosure its expression has been associated with progression of disease and metastasis. SPTAN1 might serve as both a ThismanuscriptispartofthePh.D.thesisofAnneAcker- tumor suppressor and promotor by several mechanisms. Its mann. tumor suppressing characteristics include maintaining cell shape and cytoskeletal architecture by interacting with other cytoskeletal proteins and enabling DNA repair. SPTAN1’s Conflicts of Interest switchboard and transporter function as well as its role eTh authors declare that they have no conflicts of interest. in apoptosis, EMT, adhesion, and migration can influence tumor growth and progression in both positive and negative directions depending on the specific regulation. Specifically, Authors’ Contributions enhanced cytoplasmic SPTAN1 is associated with neoplasia and progression. er Th efore, SPTAN1 can have a broad impact Anne Ackermann prepared the original dra,ft generated the on cell dynamics and tumor development. Most importantly figures, and edited the manuscript. Angela Brieger concep- and promising for clinical practice, SPTAN1 has the potential tualized the idea, supervised the project, and cowrote and to be used as a tumor marker for progression as well as a reviewed the paper. marker for therapy decisions. In this regard, the following features are particularly important when considering its relevance: (a) cellular localization, (b) level of expression Acknowledgments in tumors, (c) isoforms, and (d) posttranslational modicfi a- tions. eTh authors apologize to those whose work was not cited SPTAN1 is comprehensively involved in cell dynamics here due to space limitations and the extensive research on and a better understanding of its mechanism of action and spectrins. They would like to thank Jasmin Ackermann and fine tuning in various processes leads not only to a better Dr. Christopher Schrecker for constructive criticism of the understanding of tumor characteristics but also beyond in manuscript. 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