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• W1515521950 abstract "The canonical Wnt cascade controls a wide spectrum of biological processes throughout embryonic development and in adult tissues. As a consequence, dysregulation of Wnt signaling can alter cell fate and stimulate cancer development in many tissues.1 Because of its centrality to stem and progenitor cell self-renewal, the core Wnt/β-catenin signaling pathway is always subverted in cancer cells to perpetuate malignant growth.2 During the adult liver regeneration, the activated β-catenin signaling drives the expression of target genes that are critical for cell cycle progression and proliferation.3 In parallel, aberrant Wnt signaling contributes to pathogenesis of hepatocellular carcinoma (HCC) by promoting tumor cell growth and survival.3 In recent years, there has been a tremendous progress of research that establishes the central role of epigenetic abnormalities including modifications of chromatin and microRNAs (miRNAs) in cancer initiation, progression, and treatment.4 Whereas somatic mutations in the Wnt pathway are often associated with cancers of a variety of tissues, including those of the gastrointestinal system, accumulating evidence has revealed the significance of epigenetic regulation of the suppressor or activator components in this signal transduction cascade.1 Active Wnt/β-catenin signaling is frequently observed in ∼70% of human HCCs.5, 6 However, genetic mutations in the components of Wnt pathway, for example AXIN1, AXIN2, and CTNNB1, are only accountable to a subset (< 40%) of human HCCs with abnormal accumulation of β-catenin.7, 8 Among the natural antagonists of the Wnt signaling pathway, the secreted frizzled-related proteins (sFRPs) and the sex-determining region Y-box (SOX) family members bind directly to extracellular Wnt ligands and nuclear β-catenin, respectively, and suppress β-catenin-mediated T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling (Fig. 1). In this issue of Journal of Gastroenterology and Hepatology, Shih and colleagues demonstrated that SOX1 was frequently downregulated through promoter hypermethylation in HCC cells and tissues by methylation-specific polymerase chain reaction (MSP),9 providing new evidence of epigenetic activation of Wnt signaling in HCC. Epigenetic activation of Wnt/β-catenin signaling in hepatocellular carcinoma (HCC). An array of Wnt pathway antagonists operating at different subcellular localizations (green ovals) has been shown to be hypersilenced by DNA and histone methylation (red and blue arrows, respectively). Some Wnt antagonists, for example AXIN2 and sFRP5 are simultaneously suppressed by both DNA and histone modifications (purple arrows). Activated oncogenic miR-155 also transcriptionally represses the negative Wnt antagonist adenomatous polyposis coli. Collectively, these epigenetic alterations release tumor-suppressive brakes on the oncogenic potency of highly active Wnt/β-catenin signaling, resulting in transcription of pro-proliferative and -survival genes such as cyclin D1 (CCND1) and c-MYC. Frequent methylation of the sFRP family members (sFRP-1, -2, and -5 but not the least homologous sFRP4) has been previously documented in ∼40–50% of human HCCs by the same laboratory.10 In parallel with the methylation pattern of the sFRP genes,10 the SOX1 promoter was also found to be hypermethylated along the hepatic carcinogenic cascade, with modest frequency of methylation in chronic hepatitis (14%), higher frequency in cirrhosis (33%), and the highest methylation observed in HCCs (57%) relative to none in control livers.9 The progressive SOX1 promoter methylation in human hepatocarcinogenesis was validated by quantitative MSP. The change in the averaged levels of promoter methylation in different tissue types has, however, not been addressed using this quantitative method. The authors further found a strong correlation between SOX1 and sFRPs methylation in HCCs and showed concordant hypermethylation in 56% (30/54) of cases. Similar to the effects of sFRP1,10 restoration of SOX1 significantly decreased TCF/LEF-dependent transcriptional activity and HCC cell growth.9 In this study, Shih et al. have clearly demonstrated that promoter hypermethylation of SOX1 and sFRPs contribute to hepatocarcinogenesis. Whereas gene mutations are mostly confined to tumor tissues, epigenetic inactivation of Wnt antagonists occurs early in inflamed and cirrhotic tissues and further accumulates in HCCs.9, 10 These findings concur with an emerging picture that epigenetic alterations often precede genetic alterations in cancer. The validated tumor-suppressive functions of SOX1 and sFRPs and their concomitant hypermethylation in early hepatocarcinogenesis further establish epigenetic silencing of Wnt antagonists as a crucial driving force in HCC.9-11 Future studies will be needed to delineate the relationship between epigenetic and genetic mechanisms in Wnt activation by investigating whether HCCs showing promoter hypermethylation harbor gene mutations of the Wnt components. Another important epigenetic mechanism underlying the suppression of Wnt antagonists in human HCCs is mediated by enhancer of zeste homolog 2 (EZH2),6 the catalytic subunit of the polycomb repressor complex 2 that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3).12 Numerous Wnt inhibitors operating at different subcellular compartments, including AXIN2, NKD1, PPP2R2B, PRICKLE1, and sFRP5 were uncovered to be concordantly silenced by EZH2-catalyzed H3K27me3 (Fig. 1), which in turn drive Wnt/β-catenin signaling and HCC cell proliferation.6 This is particularly intriguing because the majority of EZH2- and β-catenin-coexpressing HCCs, which constitutes more than one third of the examined cases (61/179), do not harbor CTNNB1/AXIN1/AXIN2 mutation,6 thus highlighting the significance and independence of Wnt activation by EZH2-mediated epigenetic mechanism in HCC. Accumulating evidence support the importance of miRNAs in the epigenetic deregulation of oncogenic signaling pathways in HCC.13 In this connection, miR-155 has been recently shown to promote hepatic oncogenesis by activating Wnt signaling.14 Activated by nuclear factor kappa B, miR-155 directly represses adenomatous polyposis coli, a negative regulator of Wnt signaling (Fig. 1) and stimulates Wnt/β-catenin-dependent hepatocarcinogenesis.14 In contrast with the aforementioned gene silencing mechanisms, emerging evidence suggest that promoter DNA hypomethylation may also participate in cancer initiation and progression via reactivation of potential tumor-causing genes.13 Recent genome-wide methylation studies in HCC tissues have revealed that ∼50–75% of the interrogated gene promoters in tumors are indeed hypomethylated, that is, showing less methylation compared with nontumor tissues.15, 16 Whether these epigenetic alterations contribute to expression of activators in Wnt or other pathways warrants further investigation. Knowledge of the molecular pathway from the etiological factors to the oncogenic signaling in HCC can be translated into therapeutic potential.17 For instance, a direct transcriptional target of androgen receptor has been shown to promote hepatocarcinogenesis through the upregulation of β-catenin/TCF signaling,18 providing a novel therapeutic target in HCC that exhibits gender disparity toward male.19 Would other risk factors like viral hepatitis or metabolic syndrome induce HCC development via epigenetic mechanisms? Would Wnt/β-catenin or other frequently deregulated signaling be met at the crossroads? Genome-wide high-resolution technologies such as chromatin immunoprecipitation coupled with next-generation sequencing or RNA sequencing will greatly facilitate the identification of target genes of specific chromatin regulators and the signaling interactions relevant to a malignant phenotype.12 The past decade has witnessed an unprecedented interest in translational medicine for cancer epigenetics research.4, 20 Given the molecular diversity and perhaps more important, the reversibility of the Wnt antagonist repression by distinct epigenetic mechanisms (Fig. 1), prudent combination of chromatin-modulating drugs in epigenetic therapy might be proved effective for the treatment of Wnt-addicted cancers such as HCC." @default.
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• W1515521950 date "2013-02-26" @default.
• W1515521950 modified "2023-10-17" @default.
• W1515521950 title "Alliance of epigenetic forces for the activation of oncogenic Wnt/β-catenin signaling" @default.
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