Comprehensive Bioinformatics Analysis of Key Methyltransferases and Demethylases for Histone Lysines in Hepatocellular Carcinoma

Abstract

Background & Aims: Methylation of lysines on histones, controlled by various methyltransferases and demethylases, is an important component of epigenetic modifications, and abnormal regulation of such enzymes serves as common events in hepatocellular carcinoma. We determined to identify important methyltransferases and demethylases that might regulate the development of hepatocellular carcinoma by bioinformatics. Methods: The Oncomine and UALCAN databases were used to retrieve mRNA expression levels of histone lysine methyltransferases and demethylases in hepatocellular carcinoma. Data analyses of genetic alterations, mainly mutations and copy number alterations, were performed on the cBioportal platform. Protein-protein interactions were established in the STRING database. Results: mRNA expression of 8 genes correlated with clinical staging and grading, whereas 4 genes indicated a role in the prognosis, all co-expressed with SEDB1 and WHSC1. Genetically, 12 genes showing an alteration rate higher than 5% were identified, and only 3 were indicative of prognosis. Copy number gains in ASH1L, SETDB1, and KDM5B might partially contribute to the upregulation of their mRNA expression. The close relationship of mutations in MLL2/MLL3 with driver gene mutations in hepatocellular carcinoma provided a rationale for further investigation. Conclusions: We identified 11 methyltransferases and demethylases for major histone lysines that might be promising research targets in the pathogenesis, development, and prediction of prognosis in hepatocellular carcinoma using bioinformatics.

Lysine demethylase 5C epigenetically reduces transcription of ITIH1 that results in augmented progression of liver hepatocellular carcinoma

“…Both genetic and epigenetic alterations play critical roles in tumorigenesis, including hepatocarcinogenesis 19 . Several key methyltransferases and demethylases, such as SETDB1, EZH2, ASH1L, WHSC1, NSD1, EHMT2, KDM1A, KDM3A, KDM3B, KDM4B, and KDM5B, have been demonstrated to be frequently upregulated in HCC tumor tissues and possibly implicated in its pathogenesis 20–22 . KDM5C has been suggested as a pan‐cancer‐driver 11 and reportedly involved in the tumorigenesis of cancers of the colon, 12 stomach, 23 and lung 24 .…”

“…19 Several key methyltransferases and demethylases, such as SETDB1, EZH2, ASH1L, WHSC1, NSD1, EHMT2, KDM1A, KDM3A, KDM3B, KDM4B, and KDM5B, have been demonstrated to be frequently upregulated in HCC tumor tissues and possibly implicated in its pathogenesis. [20][21][22] KDM5C has been suggested as a pan-cancer-driver 11 and reportedly involved in the tumorigenesis of cancers of the colon, 12 stomach, 23 and lung. 24 Importantly, KDM5C has also been reported to augment migration, invasion and epithelial-mesenchymal transition of HCC cells.…”

Activating transcription factor 2 promotes the progression of hepatocellular carcinoma by inducing the activation of the WHSC1‐mediated TOP2A/PI3K/AKT axis

“…An elevated mRNA level of WHSC1 is correlated with reduced survival and is a biomarker indicating unfavorable prognosis of patients with HCC. 35 Thus, the oncogenic role of WHSC1 was validated in HCC cells.…”

“…Further upregulation of WHSC1 increased the expression of TOP2A and promoted the phosphorylation of PI3K and AKT, which consequently restored the malignant behaviors of HepG2 cells. An elevated mRNA level of WHSC1 is correlated with reduced survival and is a biomarker indicating unfavorable prognosis of patients with HCC 35 . Thus, the oncogenic role of WHSC1 was validated in HCC cells.…”

Construction of a Myc-associated ceRNA network reveals a prognostic signature in hepatocellular carcinoma

“…The UALCAN database ( http://ualcan.path.uab.edu/ ) is a data-mining platform, in which the methylation of DE mRNA in tumors can be queried. 106 , 107 , 108 In this study, we used the UALCAN database to analyze SEC14L2 methylation in liver cancer tissues and paracancerous tissues. The MethSurv database ( https://biit.cs.ut.ee/methsurv/ ) is an open website used to obtain CpG methylation data, 109 and it contains significant information about a single CpG.…”