Long non-coding RNA in glioma: novel genetic players in temozolomide resistance Long non-coding RNA in glioma: novel genetic players in temozolomide resistance
Roh, Jungwook; Im, Mijung; Kang, JiHoon; Youn, BuHyun; Kim, Wanyeon
ANIMAL CELLS AND SYSTEMS 2023, VOL. 27, NO. 1, 19–28 https://doi.org/10.1080/19768354.2023.2175497 Long non-coding RNA in glioma: novel genetic players in temozolomide resistance a# a# b c a,d Jungwook Roh , Mijung Im , JiHoon Kang , BuHyun Youn and Wanyeon Kim a b Department of Science Education, Korea National University of Education, Cheongju-si, Republic of Korea; Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA, USA; Department of Biological Sciences, Pusan National University, Busan, Republic of Korea; Department of Biology Education, Korea National University of Education, Cheongju-si, Republic of Korea ABSTRACT ARTICLE HISTORY Received 25 November 2022 Glioma is the most common primary malignant brain tumor in adults and accounts for Revised 15 January 2023 approximately 80% of brain and central nervous system tumors. In 2021, the World Health Accepted 27 January 2023 Organization (WHO) published a new taxonomy for glioma based on its histological features and molecular alterations. Isocitrate dehydrogenase (IDH) catalyzes the decarboxylation of KEYWORDS isocitrate, a critical metabolic reaction in energy generation in cells. Mutations in the IDH genes Isocitrate dehydrogenase; interrupt cell diﬀerentiation and serve as molecular biomarkers that can be used to classify long non-coding RNA; gliomas. For example, the mutant IDH is widely detected in low-grade gliomas, whereas the glioma; temozolomide wild type is in high-grade ones, including glioblastomas. Long non-coding RNAs (lncRNAs) are resistance epigenetically involved in gene expression and contribute to glioma development. To investigate the potential use of lncRNAs as biomarkers, we examined lncRNA dysregulation dependent on the IDH mutation status. We found that several lncRNAs, namely, AL606760.2, H19, MALAT1, PVT1 and SBF2-AS1 may function as glioma risk factors, whereas AC068643.1, AC079228.1, DGCR5, FAM13A-AS1, HAR1A and WDFY3-AS2 may have protective eﬀects. Notably, H19, MALAT1, PVT1, and SBF2-AS1 have been associated with temozolomide resistance in glioma patients. This review study suggests that targeting glioma-associated lncRNAs might aid the treatment of glioma. Introduction reclassiﬁes gliomas into adult-type diﬀuse gliomas, pedi- Gliomas are primary brain tumors derived from neuro- atric-type diﬀuse LGGs, pediatric-type diﬀuse HGGs, cir- glial stem cells or neuroglial progenitor cells (Weller cumscribed astrocytic gliomas, and ependymal tumors et al. 2015). The grading of gliomas based on histological (Horbinski et al. 2022). This system also classiﬁes features has been debated for decades by technical gliomas according to isocitrate dehydrogenase (IDH) limitations and diﬀerent opinions. However, recent mutation status and uses various molecular markers to advances in molecular genetics have revealed novel classify subgroups by their molecular characteristics changes in several tumors and have changed the diag- (Komori 2022). nostic paradigm for tumors of the central nervous IDH is an essential enzyme involved in major meta- system (CNS). Molecular diagnosis was ﬁrst introduced bolic processes such as the TCA cycle, glutamine in the World Health Organization (WHO) CNS glioma metabolism, adipogenesis, and redox regulation and classiﬁcation system published in 2016 (Louis et al. has three isoforms, and IDH1 and IDH2 are used as 2016; Louis et al. 2021). According to this system, glioma biomarkers (Koh et al. 2004; Lee et al. 2004; grades 1 and 2 are low-glioma grades (LGGs), and Yan et al. 2009). The most common mutation detected grades 3 and 4 are high-glioma grades (HGGs) (Chen in human IDH1 replaces arginine at position 132 by et al. 2022). In addition, a new classiﬁcation in the histidine (R132H), whereas the one in human IDH2 WHO published in 2021 incorporates more molecular does arginine at 172 by lysine (R172 K) (Dang et al. alterations into the diagnosis of many tumors and 2009; Yan et al. 2009). Wildtype IDH enzymes convert CONTACT BuHyun Youn firstname.lastname@example.org Department of Biological Sciences, Pusan National University, Busandaehak-ro 63beon-gil 2, Geumjeong-gu, Busan 46241, Republic of Korea; Wanyeon Kim email@example.com Department of Biology Education, Korea National University of Education, 250 Taeseongtabyeon-ro, Gangnae-myeon, Heungdeok-gu, Cheongju-si, Chungbuk 28173, Republic of Korea Authors contributed equally. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 20 J. ROH ET AL. isocitrate to α-ketoglutarate (α-KG). However, the Li et al. 2021). In this review, to address the issue of mutant IDHs have changed their substrate speciﬁcity, TMZ resistance, we summarize the eﬀects of lncRNA converting α-KG to 2-hydroxyglutarate (2-HG). The con- dysregulation according to IDH mutation status in sequent excessive accumulation of 2-HG leads to glioma. glioma development and their malignant progression, associated metabolic alterations, DNA methylation, IDHs as classiﬁcation biomarkers in glioma and reactive oxygen species (ROS) production (Dang et al. 2009; Lu et al. 2012; Turcan et al. 2012). The IDH is a representative biomarker of glioma classiﬁ- majority of LGG patients have mutations in IDH, and cation, and WHO primarily classiﬁes gliomas according a signiﬁcant correlation has been reported between to IDH mutation status. IDH is an enzyme that catalyzes IDH mutation and improved overall survival in LGG the reversible oxidative decarboxylation of isocitrate, (Rickert 1987; Youssef and Miller 2020). WHO CNS which results in the production of carbon dioxide and grade 4 glioblastoma can be classiﬁed as primary or α-KG in the TCA cycle during glucose metabolism, secondary. Most primary and secondary glioblastomas which in turn, is coupled with the transformation of are of the IDH-wildtype or mutant types, respectively, NAD(P) to NAD(P)H (Zhao et al. 2009). In mammals, and overall survival is better for the secondary type IDH exists in three isoforms: IDH1 is present in the cyto- (Nobusawa et al. 2009; Wick et al. 2009; Sun et al. plasm and peroxisomes, and IDH2 and IDH3, in the mito- 2013). However, diagnoses of glioma based on the chondrial matrix (Leighton et al. 1969). IDH1 and IDH2 mutation status of the IDH genes alone overlook the use NADP as a cofactor to produce α-KG and NADPH, various origins and characteristics of glioma. Therefore, and the generated NADPH protects cells from oxidative an understanding of the molecular mechanism of damage by participating in key ROS scavenging pro- glioma is required for accurate diagnosis and cesses such as biosynthetic reactions and glutathione treatment. disulﬁde reduction (Hurley et al. 1991; Xu et al. 2004; Long non-coding RNAs (lncRNAs), which do not Itsumi et al. 2015). IDH3 plays a central role in energy encode proteins and are more than 200 nucleotides in production in the TCA cycle by generating α-KG and length, regulate cellular biological processes in cancer NADH using NAD as a cofactor (Reitman and Yan such as cell proliferation, metastasis, invasion, motility, 2010). Both IDH1 and IDH2 form a homodimer, and drug resistance, and their intracellular locations whereas IDH3 holoenzyme is multimeric and assembled reﬂect their functions (Seo et al. 2019; Seo et al. 2021; with multiple subunits of α, β, and γ encoded by IDH3a, Chen et al. 2022). Nuclear lncRNAs aﬀect gene IDH3b, and IDH3c, respectively (MacDonald et al. 2013). expression at the transcriptional level, regulating In diﬀuse gliomas, the IDH1-mutant type is the most histone modiﬁcation, DNA methylation and chromatin common and observed in more than 90% of cases. The remodeling (Marín-Béjar et al. 2013; Zhang et al. 2014; IDH2-mutant type is observed in approximately 10% of Chu et al. 2015; Do et al. 2019). On the other hand, cyto- cases, but the IDH3-mutant type has never been plasmic lncRNAs are competitive endogenous RNAs observed (Waitkus et al. 2018). (ceRNAs) that interact with mRNAs and miRNAs to epi- In cases of IDH1 mutation, the homodimer formed by genetically regulate gene expression at the post-tran- two IDH1-mutant monomers does not have enzymatic scriptional and translational levels. Recent studies activity, but the heterodimer composed of the IDH-wild- suggest that dysregulations of lncRNA can result in the type and mutant monomer has enzymatic activity initiation, progression, and other malignant phenotypes suﬃcient to convert α-KG to 2-HG (Dang et al. 2009; of glioma (Karreth et al. 2011; Tay et al. 2014; Shao et al. Yang et al. 2010). IDH is one of the most studied genes 2016; Peng et al. 2018; Zhou et al. 2020). in glioma development, and cancers with IDH1 or IDH2 O -methylguanine-DNA methyltransferase (MGMT) mutations produce 10–100 times more 2-HG than methylation, 1p/19q co-deletion, IDH, and epidermal those with the IDH1 or IDH2 wildtype (Ward et al. growth factor receptor have been widely used as 2010; Leeper et al. 2015). IDH1 mutation converts α-KG glioma biomarkers (McNamara et al. 2013;Ludwig to 2-HG, which accumulates in the cytoplasm, and and Kornblum 2017). Recently, it has been demon- thereby releases carbon from the TCA cycle. This cycle strated that lncRNAs might also function as molecular utilizes metabolic reprogramming to compensate for biomarkers in glioma (Peng et al. 2018). For example, ﬂuctuations in metabolic pathways; for example, gluta- lncRNA dysregulation has been shown to be corre- mate dehydrogenase converts glutamine to α-KG, lated with glioma malignancy and associated with which replenishes the TCA cycle (Hausinger 2004; resistance to radiotherapy and temozolomide (TMZ) Loenarz and Schoﬁeld 2008; Xu et al. 2011). In addition (Lu et al. 2020;Chae etal. 2021;Kuang et al. 2021; to the metabolic changes, the hypermethylation of ANIMAL CELLS AND SYSTEMS 21 CpG islands is also aﬀected by IDH mutations. The tumor behavior and prognosis. LncRNA AC068643.1 is glioma-speciﬁc methylation pattern provides clues more highly expressed in IDH-mutant glioblastomas regarding the pathogenesis of IDH-mutant gliomas. than in the wildtype. The expression levels of DNA methylation is regulated by methyltransferase AC068643.1 are positively correlated with the protein and demethylase. During demethylation, ten-eleven levels of bone morphogenetic protein (BMP) and myos- translocation methylcytosine dioxygenase (TET) con- tatin (MSTN), and it has been experimentally demon- verts 5-methylcytosine to cytosine in an iron- and α- strated that both BMP and MSTN directly stimulate KG-dependent manner. Furthermore, the activity of AC068643.1 expression (Huang et al. 2020). BMP inhibits TET might be inhibited by 2-HG due to its structural simi- cell proliferation in glioblastoma and astrocytic glioma, larity to α-KG (Xu et al. 2011; Lee et al. 2021). Histone and a BMP-like synthetic is considered a non-cytotoxic methylation status is regulated by histone methyltrans- therapeutic that might prevent glioma growth and ferases such as euchromatic histone lysine methyltrans- recurrence. Altogether, these results suggest that ferase 1 (EHMT1), EHMT2, SET nuclear proto-oncogene AC068643.1 can function as a protective lncRNA in glio- (SET), and enhancer of zeste 2 polycomb repressive blastoma patients (González-Gómez et al. 2014; Sach- complex 2 subunit (EZH2), and demethylases such as deva et al. 2019). lysine demethylase 1A (KDM1A) and KDM4A (Chowdh- Diﬀerentially expressed lncRNAs were identiﬁed ury et al. 2011; Hayward and Cole 2016; Katoh 2016; using GSE107850, a dataset of glioma patients that Rahman et al. 2021). Like TET, histone demethylases underwent surgical excision and TMZ treatment. A such as KDM4 and KDM5 are inhibited by high levels risky lncRNA AL606760.2 and two protective lncRNAs, of 2-HG (Chowdhury et al. 2011). Many studies report FAM13A antisense RNA 1 (FAM13A-AS1) and that histone methylation markers accumulate in AC079228.1, were suggested as predictors of TMZ various cancers harboring a mutant IDH gene. Also, inhi- eﬃcacy in IDH-mutant type LGGs (Li et al. 2021). Further- bition of histone demethylation by 2-HG leads to more, levels of AL606760.2 and Smad2, which mediates impaired cell diﬀerentiation, which might be associated transforming growth factor (TGF)-beta signaling, are with the tumorigenesis of IDH-mutant glioma (Lu et al. positively correlated. Thus, AL606760.2 appears to regu- 2012). late intracellular processes such as cell proliferation, IDH is an essential enzyme for energy metabolism apoptosis, and diﬀerentiation (Abdel-Wahab et al. associated with the TCA cycle, and mutated IDH causes 2002). On the other hand, FAM13A-AS1 is involved in 2-HG accumulation, hypermethylation, and oxidative decreasing cell proliferation and diﬀerentiation, and its damage. Because of these alterations, it is reasonable levels were found to be signiﬁcantly correlated with to classify glioblastomas by IDH mutational status. The UBR5 levels (an E3 ubiquitin-protein ligase) (Jiang et al. new molecular markers including IDH will help diagnose 2011; Gudjonsson et al. 2012). The two cancer-related and eﬀectively treat gliomas. genes, pre-mRNA processing factor 40 homolog B (PRPF40B) and zinc ﬁnger homeobox 3 (ZFHX3), were suggested to be potential target mRNAs of lncRNA LncRNAs and IDH mutations in glioma AC079228.1. PRPF40B is a splicing gene that directly In brain tumors, IDH mutation status is known to be interacts with splicing factor 1 (SF1), and associated associated with a patient’s prognosis of brain tumors with U2 small nuclear RNA auxiliary factor 1 (U2AF1). and with a well-known molecular biomarker of glioma ZFHX3 acts as a transcription factor for regulation of (Turcan et al. 2012). Reportedly, lncRNAs are epigeneti- myogenic and neuronal diﬀerentiation and inhibition cally involved in gene expression regulation and treat- of cell cycle progression (Benjamin et al. 2009; Gudb- ment resistance in brain tumors (Mercer et al. 2009). jartsson et al. 2009). Furthermore, accumulating evidence suggests that In another study, lncRNAs diﬀerentially expressed in lncRNAs function as ceRNAs that regulate gene IDH-mutant and IDH-wildtype glioma samples obtained expression and alter cell biological properties such as from several CCGA, TCGA, and GSE16011 datasets were cell viability, proliferation, motility, and invasion (Do analyzed using the LNCipedia database (Chen et al. and Kim 2018; Seo et al. 2020). 2020). Multivariate Cox regression analysis of the prog- nostic performances of diﬀerentially expressed lncRNAs identiﬁed H19 and plasmacytoma variant translocation Dysfunction of lncRNAs according to IDH- 1 (PVT1) as risky lncRNAs and highly accelerated region mutant status 1A (HAR1A) as a protective lncRNA in glioma. LncRNA Glioblastoma can be classiﬁed as IDH-wildtype or H19 promotes angiogenesis in gliomas by increasing mutant types, each of which is associated with a distinct the expressions of hypoxia inducible factor 1 subunit 22 J. ROH ET AL. alpha (HIF-1α) and vascular endothelial growth factor highly expressed in IDH-wildtype than in IDH-mutant (VEGF) through targeting miR-138. In glioma, H19 can glioma and its knockdown in glioblastoma upregulates also target miR-342 and upregulate the Wnt5a/β- miR-338-3p, but downregulates EGF-like domain mul- catenin pathway to promote cell proliferation and tiple 7 (EGFL7), thereby inhibiting angiogenesis migration (Liu et al. 2020; Zhou et al. 2022). Also, (Cancer Genome Atlas Research Network et al. 2015; lncRNA PVT1 targets miR-200a to regulate the cell Yu et al. 2017; Zhang et al. 2021). cycle and promote cell proliferation and invasion An analysis of the CGCA database revealed lncRNA (Zhang et al. 2019). On the other hand, lncRNA HAR1A WDFY3 antisense RNA 2 (WDFY3-AS2) is expressed at acts to suppress the progression of diﬀuse glioma and low levels in IDH-wildtype gliomas. Kaplan-Meier analy- is expressed at low levels in glioma. In addition, glioma sis showed that WDFY3-AS2 overexpression was associ- patients with high PVT1 expression or low HAR1A ated with longer overall survival than low WDFY3-AS2 expression is reported to be prognostic of poor survival expression, and Cox regression analysis showed its in glioma patients. Moreover, the down-regulation of expression was independently correlated with overall PVT1 and up-regulation of HAR1A improved the survival survival. In addition, gene ontology (GO) and gene set of glioma patients that received chemotherapy and enrichment analysis (GSEA) revealed that WDFY3-AS2 radiotherapy. These ﬁndings imply that these lncRNAs is involved in the regulation of synaptic transduction, play critical roles in diﬀuse glioma progression and glutamate receptors, and TNF signaling pathways (Wu that PVT1 and HAR1A should be explored as promising et al. 2018). biomarkers for diagnosis, prognosis, and targeted LncRNA DiGeorge syndrome critical region gene 5 therapy (Zou et al. 2017). (DGCR5) plays cancer-dependent roles. For example, although DGCR5 levels were unrelated to WHO malig- nancy grade in glioma, they were more downregulated LncRNA dysfunction in IDH-wildtype gliomas in IDH-wildtype glioma than in IDH-mutant glioma. Fur- IDH-wildtype gliomas are associated with poor prog- thermore, DGCR5 increased the levels of Smad7 and noses and high CNS grades. Metastasis-associated lung phosphatase and tensin homolog (PTEN) by sponging adenocarcinoma transcript 1 (MALAT1) is an overex- miR-21 and miR-23a, respectively, in glioma cells. It is pressed lncRNA in glioblastoma and promotes cell also reported that Smad7 inhibits the migratory and growth and tumorigenesis. For example, it has been invasive activities of glioma, and PTEN inhibits cell pro- demonstrated that lncRNA MALAT1 promotes the liferation and enhances apoptosis. Patients with low expression of SRY-box transcription factor 2 (SOX2) by DGCR5 expression levels show poorer overall survival suppressing miR-129 to promote glioma stem cell viabi- (He et al. 2020). lity, proliferative abilities, and tumorigenesis (Xiong et al. 2018). In addition, methyltransferase 3 (METTL3), which TMZ resistance by lncRNAs according to IDH upregulates the expression of MALAT1 through N - mutation status methyladenosine (m A) modiﬁcation, is also associated with poor prognosis. It was also demonstrated that Glioma classiﬁcation based on histological features and MALAT1 overexpression promotes the malignant IDH mutation status helps with diagnosis and prognosis. glioma phenotype by inducing epithelial–mesenchymal Although advances in techniques, technologies, surgical transition (EMT) and tumor necrosis factor (TNF) signal- resection, chemotherapy, and radiotherapy have signiﬁ- ing through nuclear factor kappa B (NF-κB) activation cantly improved treatment eﬃcacy outcomes fall far (Chang et al. 2021). short of satisfactory. Furthermore, accumulating evi- Furthermore, lncRNA SBF2 antisense RNA 1 (SBF2- dence indicates lncRNA dysregulations are involved in AS1), which plays an oncogenic role in various tumors, glioma chemo- and radioresistance. This review com- may function as a biomarker in diﬀuse LGG. Kaplan- piles several diﬀerentially expressed lncRNAs in IDH- Meier analysis showed that the prognosis of LGG mutant and IDH-wildtype gliomas, and it has been patients with high SBF2-AS1 expression was poorer shown that lncRNAs SBF2-AS1, PVT1, MALAT1, and H19 than those with low expression. Cox regression analysis signiﬁcantly contribute to the induction of TMZ showed that SBF2-AS1 is an independent prognostic resistance. factor of poorer overall survival in LGG (Zhang et al. TMZ is a lipophilic anticancer drug, which is widely 2021). Most LGGs are IDH mutant type, and only some used to treat brain tumors. TMZ can be readily delivered are IDH-wildtype. However, the molecular and clinical to brain tissues as it crosses the blood–brain barrier and characteristics of IDH-wildtype LGG are similar to those induces cell death by causing single- or double-strand of glioblastoma. It is reported that SBF2-AS1 is more breaks by incorporating mismatched base pairs. ANIMAL CELLS AND SYSTEMS 23 However, more than 50% of glioma patients do not reportedly, its knockdown eﬀectively promotes glioma respond to TMZ, and lncRNAs appear to be involved in cell sensitivity to TMZ. PVT1 and miR-365 expressions TMZ resistance by regulating chemoresistance-associ- are negatively correlated, and the overexpression of ated gene expression, enhancing cell survival, and inhi- miR-365 suppresses TMZ resistance in glioma cells. biting apoptosis (Lee 2016). Furthermore, numerous PVT1 competitively binds to miR-365 and positively studies have suggested that lncRNA might act as a regulates the expression of E74 like ETS transcription ceRNA of miRNA to modulate the expressions of target factor 4 (ELF4), which contributes to the induction of genes (Salmena et al. 2011). The interaction between glioma stemness and TMZ resistance (Bazzoli et al. lncRNA and miRNA might also inﬂuence TMZ resistance 2012; Gong et al. 2021). MALAT1 is frequently overex- in glioma cells. It is reported that sponging of miR-151a- pressed in IDH-wildtype gliomas and enhances resist- 3p by lncRNA SBF2-AS1, which is more highly expressed ance to TMZ administration by regulating the in IDH-wildtype than IDH-mutant gliomas, is responsible expressions of miRNAs. Several studies have shown for TMZ resistance in glioma cells (Zhang et al. 2019). that miR-203 contributes to reduced chemoresistance Furthermore the transcription factor, zinc ﬁnger E-box in various cancers (Li et al. 2011; Lin et al. 2016; Zhang binding homeobox 1 (ZEB1), might increase SBF2-AS1 et al. 2016). Furthermore, MALAT1 promotes glioma expression by binding to its promotor region, and the cell proliferation and TMZ resistance by decreasing resulting high level of SBF2-AS1 downregulates miR- miR-203 expression and increasing the expression of 151a-3p and the subsequent upregulation of X-ray thymidylate synthase (TS), a potent cancer chemother- repair cross complementing 4 (XRCC4), a target of miR- apy target (Chu et al. 2003; Chen et al. 2017). In addition, 151a-3p. XRCC4 promotes DNA double-strand break MALAT1 downregulates miR-101, consequently increas- repair and thus enhances cell survival and inhibits apop- ing resistance to TMZ in glioma cells by increasing glyco- tosis in glioma cells in response to TMZ treatment. Fur- gen synthase kinase 3β (GSK-3β) levels. Also, increased thermore, it has been shown that SBF2-AS1 depletion GSK-3β expression might be associated with resistance reduces the level of XRCC4, delays the repair of TMZ- to TMZ and poor prognosis in glioma patients by induced DNA damage, and increases glioma cell sensi- decreasing MGMT promoter methylation and thus upre- tivity to TMZ. PVT1 is a known oncogene in various gulation of MGMT (Pyko et al. 2013; Tian et al. 2016; Cai cancers, including glioma. It is expressed at higher et al. 2018). MALAT1 also regulates TMZ resistance by levels in IDH-mutant than in IDH-wildtype gliomas and modulating multidrug resistance-related genes. The Figure 1. Mechanisms of lncRNAs inducing TMZ resistance. H19 is involved in induction of glioma cell viability and survival through upregulation of MDR1, MRP1, and ABCG2 and activation of NF-κB signaling, responsible for induction of TMZ resistance (Jiang et al. 2016; Duan et al. 2018). MALAT1 is associated with glioma cell proliferation, viability, and invasion through regulation of ceRNA net- works with miRNAs, upregulation of multidrug resistance-related genes, and regulation of ZEB1, which might contribute to glioma TMZ resistance (Chu et al. 2003; de Cremoux et al. 2007; Pyko et al. 2013; Tian et al. 2016; Chen et al. 2017; Li et al. 2017; Cai et al. 2018; Dong et al. 2019). PVT1 and SBF2-AS1 play oncogenic roles in induction of glioma stemness and cell survival, respectively, through regulation of ceRNA networks, resulting in TMZ resistance in glioma cells (Bazzoli et al. 2012; Zhang et al. 2019; Gong et al. 2021). 24 J. ROH ET AL. Figure 2. Therapeutic strategies targeting lncRNAs. Downregulation of risky lncRNAs such as AL606760.2 (Li et al. 2021), H19 (Chen et al. 2020), PVT1 (Chen et al. 2020), MALAT1 (Xiong et al. 2018), and SBF2-AS1 (Zhang et al. 2021) and upregulation of protective lncRNAs such as AC068643.1 (Huang et al. 2020), AC079228.1 (Li et al. 2021), FAM13A-AS1 (Li et al. 2021), HAR1A (Chen et al. 2020), DGCR5 (He et al. 2020), and WDFY3-AS2 (Wu et al. 2018) might help predict prognosis in glioma. downregulation of MALAT1 reduces the mRNA plus drug treatment. However, the discovery of expression levels of multidrug resistance-related pro- lncRNAs, known to induce TMZ resistance, does not teins such as multidrug resistance protein 1 (MDR1), completely explain the diﬃculties of treating patients multidrug resistance protein 5 (MRP5), and lung–resist- with TMZ-resistant glioma. Nonetheless, targeting ance related protein 1 (LRP1), which are important regu- these lncRNAs is a promising way of reducing TMZ lators of chemoresistance, and also reduces glioma cell resistance. sensitivity to TMZ. In addition, MALAT1 is involved in EMT induction and thus regulates glioblastoma cell sen- Conclusions sitivity to TMZ. The downregulation of MALAT1 decreases TMZ resistance by reducing the expression The dysregulation of lncRNA contributes to the develop- level of ZEB1, an EMT-related protein that increases ment of several types of cancer, and lncRNA promotes cancer cell motility and invasiveness (de Cremoux et al. glioma development and induces chemo- and radiore- 2007; Li et al. 2017; Dong et al. 2019). H19 is highly sistance. IDH mutation status is a widely-accepted bio- expressed in IDH-mutant gliomas and involved in TMZ marker for glioma classiﬁcation, but additional markers resistance by regulating multidrug resistance genes, are desired to determine eﬀective treatment strategies. and its levels are elevated in TMZ-resistant glioma This review focuses on risky and protective lncRNAs cells. Inhibition of H19 downregulates the expressions according to IDH mutation status and the mechanisms of several multidrug resistance genes such as MDR1, involved in TMZ resistance. We suggest ﬁve lncRNAs MRP1, and ATP-binding cassette super-family G acting as risk factors, namely, AL606760.2, H19, member 2 (ABCG2) in TMZ-resistant cells at the mRNA MALAT1, PVT1, and SBF2-AS1, and another six protective and protein levels, which suggests H19 plays an impor- lncRNAs, that are AC068643.1, AC079228.1, DGCR5, tant role in the induction of TMZ resistance in glioma FAM13A-AS1, HAR1A, and WDFY3-AS2. The risky H19, cells (Jiang et al. 2016). Furthermore, oxidative stress MALAT1, PVT1, and SBF2-AS1 increase TMZ resistance induces H19 expression and thus increases cell survival (Figure 2). Identifying these risky or protective lncRNAs and viability by activating NF-κB signaling, which accom- should help predict prognosis in glioma. Determining panies the acquisition of TMZ resistance by glioma cells the dysregulation statuses of lncRNAs associated with (Duan et al. 2018). TMZ resistance should aid the development of promis- In glioma, increased TMZ resistance, conferred by the ing pharmacological targets. Therefore, therapeutic upregulations of risky lncRNAs such as H19, MALAT1, strategies targeting the dysregulation of lncRNA accord- PVT1, and SBF2-AS1 (Figure 1), is likely to play a key ing to IDH mutation status will help improve the prog- role in the therapeutic eﬃcacy of surgical resection noses of glioma patients. 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