Demethylation at enhancer upregulates MCM2 and NUP37 expression predicting poor survival in hepatocellular carcinoma patients

Abstract

Background Identification of novel biomarker is important for development of molecular-targeted therapy agents for patients with hepatocellular carcinoma (HCC). This study aims to identify potential prognostic biomarkers and investigate epigenetic mechanism of HCC development. Methods Public bulk-RNA seq datasets and proteomic dataset were screened for identification of potential prognostic biomarkers for HCC patients. Public methylomic datasets were analyzed for deciphering the epigenetic mechanism regulating HCC-associated gene expression. Immunoblotting, immunohistochemistry, real-time PCR, and pyrosequencing were used to validate the findings from bioinformatic analyses. Results Minichromosome maintenance complex component 2 (MCM2) and nucleoporin 37 (NUP37) were overexpressed in human HCC tissues and hepatoma cell lines. MCM2 significantly positively correlated with NUP37 expression. Higher expression of MCM2 or NUP37 was significantly associated with advanced tumor stage and worse overall survival in 3 large independent HCC cohorts (n = 820). MCM2 and NUP37 overexpression are independent prognostic risk factors for HCC patients. Demethylation at an enhancer of MCM2 gene was a common event in patients with HCC, which significantly negatively correlated with MCM2 and NUP37 mRNA expression. Conclusions Demethylation at enhancer regulates MCM2 and NUP37 expression in HCC. MCM2 and NUP37 are promising prognostic biomarkers and potential targets for epigenetic therapy in HCC patients.

Epigenetic dysregulation-mediated COL12A1 upregulation predicts worse outcome in intrahepatic cholangiocarcinoma patients

“…Accumulating evidence suggests that epigenetic dysregulation modulates liver cancer development by regulating tumor-associated gene expression [ 20 – 23 ]. Unlike promoter/enhancer demethylation-mediated upregulation of ITPR3, MCM2 and NUP37 in hepatocellular carcinoma [ 20 , 21 ]. In this study, we first revealed that DNA methylation degree of COL12A1 promoter/enhancer was not demethylated in iCCA relative to the adjacent nontumor samples, indicating that COL12A1 upregulation is independent of the methylation level of its promoter/enhancer region in clinical iCCA.…”

“…Re-analyses of DNA methylation datasets GSE156299 [ 35 ] and TCGA-CHOL [ 6 ] were performed to decipher the methylation patterns of COL12A1 gene in iCCA and nontumor liver tissues. The raw data of DNA methylation were processed using minifi (version 1.38.0) as previously described [ 21 , 36 ]. Weighted gene co-expression network analysis (WGCNA) was performed for weighted correlation network analysis of gene expression patterns in iCCA [ 37 ].…”

Histone Chaperones and Digestive Cancer: A Review of the Literature

“…In addition to the above-mentioned histone chaperones, the roles of other histones in digestive cancers are being researched. MCM2, a well-recognized proliferation marker and histone chaperone, is highly expressed in HCC, EC, GC, and CRC, and negatively correlates with their prognosis [ 155 , 156 , 157 , 158 ]. Interestingly, less is known about the regulatory network mechanism of MCM2 in digestive cancer.…”

Correction: Demethylation at enhancer upregulates MCM2 and NUP37 expression predicting poor survival in hepatocellular carcinoma patients

“…Following publication of the original article [ 1 ], we have been notified that the Figure 2 was published incorrectly. Also, the Figures 2 and 7 captions should be extended and Funding note needs to be corrected.…”