Epigenetic regulation of long non-coding RNAs in gastric cancer

Abstract

Gastric cancer is one of the most common cancers and is the second leading cause of cancer mortality worldwide. Therefore, it is urgent to explore new molecular biomarkers for early diagnosis, early treatment and prognosis for gastric cancer patients. Recently, increasing evidence has shown that epigenetic changes, such as aberrant DNA methylation, histone modifications, and noncoding RNAs (ncRNAs) expression, play substantial roles in the development and progression of malignancies. Among these changes, long non-coding RNAs (lncRNAs), a novel class of ncRNAs, are emerging as highly versatile actors in a variety of cellular processes by regulating gene expression at the epigenetic level as well as at the transcriptional and post-transcriptional levels. Hundreds of lncRNAs become dysregulated in the various pathological processes of gastric cancer, and multiple lncRNAs have been reported to function as tumor-suppressors or oncogenes, although the underlying mechanisms are still under investigation. Here, we provide an overview of the epigenetic regulation of chromatin and the molecular functions of lncRNAs; we focus on lncRNA-mediated epigenetic regulation of cancer-related gene expression in gastric cancer, as well as discuss the clinical implications of lncRNAs on epigenetic-related cancer treatments, which may contribute helpful approaches for the development of new potential strategies for future diagnosis and therapeutic intervention in human cancers.

Keywords: DNA methylation; epigenetic regulation; gastric cancer; histone modification; lncRNAs.

Figure 1. LncRNAs mediate DNA methylation of target genes

(A) Hypoxia-induced AK058003 up-regulates SNCG expression by decreasing DNA methylation in its CpG islands and promoting GC metastasis and invasion. (B) HOTTIP increases HoxA13 expression to enhance GC progression not only by down-regulating DNA methylation at the E1 site but also by recruiting MLL1 and WDR5 to control histone H3K4 methylation at the E1 site. (C) HOXA11-AS functions as a scaffold and recruits EZH2, LSD1 and DNMT1 to decrease E2F1 and p21. HOXA11-AS also functions as a molecular sponge for miR-1297 and antagonizes its repressive function on EZH2 translation, which results in cell cycle progression and cell proliferation in GC.

Figure 2. LncRNAs mediate histone modifications of target genes

(A) HOTAIR recruits EZH2 and the SUZ12 complex to silence target genes via H3K27 trimethylation and thereby promotes GC progression. (B) MALAT1 up-regulates EGFL7 expression, which is related to GC invasion and migration by altering the level of H3 histone acetylation in its promoter region. (C) GClnc1 coordinates WDR5 and KAT2A localization and specifies the histone modification pattern to increase SOD2 expression during GC tumorigenesis. (D) SP1-activated LINC00673 represses KLF2 and LATS expression by functioning as a scaffold for LSD1 and EZH2 to enhance GC cell proliferation and invasion.

Figure 3. LncRNAs silence cyclin-dependent protein kinase inhibitors (CKIs) by interacting with histone modification machineries to control the cell cycle

Sp1-activated LINC00668, PVT1, LINC00152, and TUG1 promote the G0/G1 phase of the cell cycle to enhance gastric cancer cell proliferation and tumorigenesis by binding to EZH2 or SUZ12 and silencing CKIs, including P12, p16, p21, p27, and p57. In addition, EZF1-AS1 promotes the G1/S phase of the cell by repressing p21 transcription through recruiting LSD1 and causing H3K4me2 demethylation at the gene promoter region.

Figure 4. LncRNAs act as inhibitors or sponges for epigenetic regulation of miRNAs

(A) HOTAIR silences miR-34a by binding to EZH2 and SUZ12, mediating H3K27 methylation and subsequently activating C-Met and Snail during GC progression. (B) ANRIL not only down-regulates miR-99a/miR-449a expression by binding EZH2 and SUZ12 in trans but also regulates mTOR and CDK6/E2F1 pathways by silencing p15INK4B and p16INK4A expression (CDK6 inhibitors) via EZH2 binding and H3K27 trimethylation in cis, which promotes CDK6 activation and GC cell proliferation.

Figure 5. LncRNA expression is epigenetically regulated in GC

(A) The DNA methyltransferase inhibitor 5-aza-CdR increases SPRY4-IT1 expression by targeting CpG islands in its promoter region and inhibiting the development of GC. (B) The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) or HDAC3 small interfering RNAs (si-HDAC3) induces FENDRR expression by targeting histone deacetylation and reducing cell invasion and migration in GC. (C) MiR-148a up-regulates MEG3 expression by recruiting DNA methyltransferase 1 (DNMT1) and decreasing methylation of the MEG3 regulatory regions (IG-DMRs), consequently reducing tumor size in GC patients.