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  • The current study aimed to understand the roles and the

    2022-05-27

    The current study aimed to understand the roles and the underlying mechanisms of XIST in LSCC, by focusing on the regulation by miR-124-3p, which was previously identified as a target of XIST [12]. We found that the XIST expression is positively correlated with the stages of LSCC in patients. Knockdown of XIST is effective in attenuating LSCC proliferation, migration and invasion. As a mechanistic study, we also identified that the regulation of XIST in LSCC is mediated by the miR-124-3p/EZH2 axis.
    Materials and method
    Results
    Discussion First, we established that the levels of XIST was markedly higher in LSCC tissues in comparison to adjacent non-cancerous cells. This expression was significantly correlated with clinical stage of LSCC. Aberrant expression has previously been observed in other cancers such as hepatocellular carcinoma [13], breast cancer [14], lung cancer [15], and ovarian cancer [16], which suggests that XIST plays a significant role in cancer pathogenesis and progression. He et al. also observed a reduction in the expression of miR-124-3p mRNA while working on hepatic carcinoma had similar findings [17]. Previous studies have demonstrated that miR-124-3p directly targets ρ-associated protein kinase 1 [18], sphingosine kinase 1 [19], forkhead box protein Q1 [20] and talin 1 [21] to inhibit migration and invasion in numerous types of tumor. Thus, the restoration of the expression of miR-124-3p may be effective therapeutic strategy for advanced cancer. We further sought to investigate the role of XIST on the aggressive phenotypes of LSCC cells using XIST knockout cells. We found XIST knockdown significantly suppressed cell growth in cells, with colony formation assays further corroborated the anti-proliferation activity of XIST knockdown in LSCC cells. This confirms the central role XIST plays in LSCC. Similar results were obtained by Hu et al. while working on XIST knockout for Q-VD Oph cancer [22]. In the current study, we established that XIST regulated expression of miR-124. Previous studies have shown that miR-124 plays a suppressive role in cancers [23]. Xiong et al. found that XIST interacted with miR-124 to modulate bladder cancer growth, invasion, and migration by targeting androgen receptor [12]. XIST has also been shown to compete endogenous RNAs (ceRNAs) to sponge miRNAs, thereby regulating gene expression [24]. We further established that miR-124 directly modulated EZH2 expression by binding miR-124 seed complementary site located in 3′UTR of EZH2. Previous studies on gastric cancer demonstrated that down-regulation of miR-124 resulted in overexpression of EZH2 and promoted tumor progression [25]. In this current study, we also established that XIST promoted tumor growth of LSCC via regulation of miR-124/EZH2 axis. We further demonstrated in this study that in knockdown of XIST suppresses tumor growth via regulation of miR-124/EZH2 axis in vivo.
    Funding
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    Consent for publication
    Conflicts of interest
    Acknowledgements
    Introduction Transcriptional regulation of gene expression is controlled primarily by the expression of DNA-binding transcription factors and chromatin remodeling [1]. Cellular critical processes such as gene expression, DNA synthesis and cell cycle progression are related to chromatin structure. Epigenetic regulations based on chromatin modifications contributes to gene expression programs in normal and cancerous cells [1,2]. Epigenetic dysregulations are now found as critical events in cancer initiation, promotion and progression [3]. Hypermethylation of DNA within CpG islands is the most well-defined alteration that is catalyzed by DNA methyltransferase (DNMT)s [3]. Promoter hypermethylation of tumor suppressor genes often occurs in the most human cancers and contributes to loss of tumor suppressor activity in these cancers [4]. In addition, there is growing evidence that histone associated chromatin modifications and their relevant enzymes are involved in tumor development [5]. A large number of histone modifications have been recognized to play a role in cancer. Polycomb group (PcG) proteins are a group of proteins which influence chromatin structure by specific histone alterations. PcG genes were initially discovered in Drosophila but then human homologs were also found with functions like Drosophila homologs. Polycomb-repressive complex (PRC) 1 and 2 are two well-characterized PcG proteins present in mammalian cells. Both PRCs have essential repressive roles on many genes which encode for transcription factors important for development of embryonic stem cells [6]. The member of PcG proteins mostly implicated in human cancer pathogenesis is EZH2, the functional catalytic subunit of PRC2 complex [7]. EZH2 is believed to regulate gene expression at transcriptional level by altering chromatin conformation, nucleosome modification and via interactions with transcription factors [8]. The EZH2 protein serves as a histone methyltransferase that catalyzes H3 methylation on lysine 27 when assembled in PRC2 complex. This process requires two other components including suppressor of zeste 12 homolog (SUZ12) and embryonic ectoderm development (EED) to form the complete multimeric structure [9].