Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer

Rezaei, Shiva; Feizi, Mohammad Ali Hosseinpour; Moaddab, Yaghoub; Safaralizadeh, Reza

doi:10.1007/s11033-020-05619-9

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…For instance, moderate and high expression levels of EZH2 are associated with unfavorable prognosis of patients with ovarian cancer [ 52 ]. Overall, EZH2 is a critical player in cancer [ 53 – 56 ] and can affect proliferation, metastasis, and therapy response of cancer cells. However, there are studies showing that EZH2 can also function as a tumor-suppressor.…”

Section: Ezh2 Signaling In Cancermentioning

confidence: 99%

The long and short non-coding RNAs modulating EZH2 signaling in cancer

et al. 2022

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Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation.

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Section: Ezh2 Signaling In Cancermentioning

confidence: 99%

The long and short non-coding RNAs modulating EZH2 signaling in cancer

et al. 2022

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“…The combination of DNA demethylating agents and EZH2 inhibitors is effective against several cancers. 57 , 58 This study is the first to demonstrate the effect of this combination in ATL. We showed that combination treatment with OR21 and EZH2 inhibitors inhibited ATL cell growth synergistically and rapidly ( Figures 1 and 6 B-C).…”

Section: Discussionmentioning

confidence: 79%

Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL

et al. 2023

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Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T cells caused by human T-cell lymphotropic virus type 1 (HTLV-1)-induced T-cell transformation. Following infection with HTLV-1, it takes several decades for HTLV-1 carriers to develop ATL. The prognosis of ATL remains poor despite several new agents are approved in the last few years. Recently, it has been noted that epigenetic abnormalities both DNA methylation and tri-methylation at histone H3Lys27 (H3K27me3) contribute to ATL leukemogenesis. Here, we investigated the effect of combination treatment with DNA demethylating agents (azacytidine (AZA), decitabine (DAC), and OR-2100 (OR21), which is silylated derivative of decitabine) and inhibitors of enhancer of zeste homolog 2 (EZH2) (EPZ-6438 and DS-3201b) which catalyze trimethylation of H3K27, in ATL. The combination of DAC and OR21 but not AZA with EZH inhibitors exhibited synergistic anti-ATL effects in vitro and in vivo concomitant with DNA demethylation and reduction of H3K27me3. The combination induced gene expression reprogramming. Dual-specificity phosphatase 5 (DUSP5), an ERK-specific phosphatase, was identified as a key molecule that mediated the inhibitory effect of combination treatment by inactivating the ERK signaling pathway. DUSP5 was downregulated by DNA methylation and H3K27me3 accumulation in the promoter region in HTLV-1-infected cells from ATL patients during ATL leukemogenesis. The present results demonstrate that dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth by restoring DUSP5, and the dual targeting of aberrant DNA and histone methylation is a feasible therapeutic approach for ATL.

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“…Histone modifications were also found to play a role in gene inactivation. EZH2 trimethylates histone H3 at lysine 27, leading to gene-expression control and contributing to SRBC gene downregulation in gastric-cancer tissues [ 161 ].…”

Section: Discussionmentioning

confidence: 99%

Gastric Cancer in the Era of Epigenetics

Christodoulidis,

Koumarelas,

Kouliou

et al. 2024

IJMS

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Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. Helicobacter pylori (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein–Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor’s metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.

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Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer

Cited by 8 publications

References 27 publications

The long and short non-coding RNAs modulating EZH2 signaling in cancer

The long and short non-coding RNAs modulating EZH2 signaling in cancer

Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL

Gastric Cancer in the Era of Epigenetics

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