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 selleck chemicals 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 Fulvestrant order reactivation of potential tumor-causing genes.[13] Recent genome-wide methylation studies in HCC tissues have revealed that ∼50–75% Vitamin B12 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.