Abstract

Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type-specific epigenomics and its clinical significance remains uncertain. We analyzed the methylomic profiles of 6 benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs) and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis-coupled proton transport, proteolysis involved in the cellular protein catabolic process and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second-generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous-type-specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC.

Original languageEnglish
Pages (from-to)355-367
Number of pages13
JournalInternational Journal of Cancer
Volume143
Issue number2
DOIs
Publication statusPublished - Jul 15 2018

Keywords

  • functional genetic interactions
  • methylation profiles
  • mucinous ovarian carcinoma
  • proteasome inhibitors
  • PSMB8
  • Epigenomics/methods
  • Humans
  • Adenocarcinoma, Mucinous/drug therapy
  • Cystadenoma, Mucinous/drug therapy
  • Gene Expression Regulation, Neoplastic/drug effects
  • Cell Survival/drug effects
  • Proteasome Inhibitors/pharmacology
  • Gastrointestinal Neoplasms/drug therapy
  • DNA Methylation
  • Ovarian Neoplasms/drug therapy
  • Proteasome Endopeptidase Complex/genetics
  • Carcinoma, Ovarian Epithelial/drug therapy
  • Oligopeptides/pharmacology
  • Cell Line, Tumor
  • Female
  • Cell Proliferation/drug effects
  • Cluster Analysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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