Epigenetics in Esophageal Cancer: From Mechanisms to Therapeutics

Abstract

2. Epigenetic Alterations in Esophageal Cancer 2.1. Role of Super-Enhancers in Esophageal Cancer cis-Regulatory elements, including promoters, enhancers, silencers, and insulators, are a key class of noncoding DNA Esophageal cancer is a leading cause of cancer-related deaths worldwide. In the past few years, the roles of epigenetics in cancer have been fully accepted. Recently, there has been an increased focus on epigenetic alterations underlying esophageal cancer carcinogenesis, with several epigenetic drug and RNA interference therapies being tested. However, the conclusion that epigenetic alterations are linked directly to an increased or decreased risk of esophageal cancer is less certain. Therefore, there is an urgent need to test novel epigenetic biomarkers for diagnostic and prognostic significance and to explore their potential as therapeutic targets. In this review, the discussion is concentrated on epigenetic alterations involving super-enhancers, DNA methylation, histone modifications, and multiple noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), and their impact on tumor growth, invasion, metastasis, and drug resistance. Then specific instances of using epigenetic drugs, such as DNA methyltransferase and histone deacetylase inhibitors, to treat esophageal cancer are described. Recent developments in miRNA-based therapeutic strategies, including antagomirs, lock nucleic acids, miRNA sponges, and microRNA replacement therapies, against esophageal cancer are also highlighted.

Genome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis

“…Although advances in clinical therapy have improved the survival of patients with localized ESCC, the high mortality of ESCC is mainly attributed to tumor metastasis. 43 Genome-wide CRISPR/Cas9 screening is a powerful tool for unbiased discovery and functional characterization of genetic alterations leading to the phenotype of interest. 4 , 44 In this study, we identified the MEST protein as an important regulator of tumor metastasis in ESCC.…”

Epigenetic Alterations from Barrett’s Esophagus to Esophageal Adenocarcinoma

“…regulates the cell cycle tumor suppressor p16INK4A promotor: BE (3-77%, mean: 29%) [12] BD (11-75%, mean: 40%) [9] EAC (16-85%, mean: 51%) [14] NSE (0-43%, mean: 9%) [9] p14ARF promotor: BE (8%) [1] EAC (0-20%, mean: 7%) [3] NSE (0%) [1] p16INK4A [21,22,24,25,27,[30][31][32][33][34][40][41][42] p14ARF [24,25,27] DAPK positive mediator of gamma-interferon-induced programmed cell death tumor suppressor BE (50%) [1], BD (53%) [1], EAC (20-70%, mean: 50%) […”

“…It has become widely acknowledged that epigenetic factors, gastrointestinal endoscopy [11]. It has become widely acknowledged that epigenetic factors, specifically those related to super-enhancers, DNA methylation, histone modifications, and non-noncoding RNAs, can be inherited somatically and can play a role in creating lasting but adaptable alterations in the development and advancement of HGD and EAC [12,13]. Early stages of cancer development involve the initiation of epigenetic modifications, which are indicative of the likelihood of progression.…”

Genome-wide identification of key regulatory lncRNAs in esophageal cancer metastasis

“…Systematic identification and functional validation of metastasis-associated long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), as well as their interactions in ESCC are urgently needed. 4 To better mimic the progression of metastasis, we performed in vitro and in vivo experiments to select highly invasive and metastatic sublines, designated I6 and LM3, respectively (Supplementary Fig. S1a).…”

“…Systematic identification and functional validation of metastasis-associated long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), as well as their interactions in ESCC are urgently needed. 4 …”