@article{b091857e38a24365a2b9670e13546eec,
title = "Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors",
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.",
keywords = "PSMB8, functional genetic interactions, methylation profiles, mucinous ovarian carcinoma, proteasome inhibitors",
author = "Liew, {Phui Ly} and Huang, {Rui Lan} and Weng, {Yu Chun} and Fang, {Chia Lang} and {Hui-Ming Huang}, Tim and Lai, {Hung Cheng}",
note = "Funding Information: Key words: methylation profiles, functional genetic interactions, mucinous ovarian carcinoma, PSMB8, proteasome inhibitors Abbreviations: BRCA: breast carcinoma; COREAD: colorectal adenocarcinoma; DM: differential methylation; DMG: differentially methylated gene; DFS: disease-free survival; EOC: epithelial ovarian cancer; GICA: gastrointestinal cancer; GBM: glioblastoma multiform; LIHC: hepatocellular carcinoma; MethylCap-seq: methyl-CpG binding domain of the MBD2 protein to capture double-stranded DNA followed by high-throughput next-generation sequencing; MuOC: mucinous type of epithelial ovarian cancer; NIK/NF-kappa B: noncanonical nuclear factor kappa-light-chain-enhancer of activated B cells; NOS: non-otherwise specified; OS: overall survival; PSMB: proteasome subunit beta; siRNA: small interference double-strand RNA; SFRP5: secreted frizzled-related protein-5; SeOC: serous type of epithelial ovarian cancer; STAD: stomach adenocarcinoma Additional Supporting Information may be found in the online version of this article. P-L.L. and R-L.H. contributed equally to this work Grant sponsor: Shuang Ho Hospital-Taipei Medical University; Grant numbers: 104TMU-SHH-07, 106TMU-SHH-04, 106TMU-SHH-14; Grant sponsor: National Health Research Institutes; Grant number: NHRI-EX106-10406BI; Grant sponsor: Ministry of Science and Technology of Taiwan (MOST); Grant number: 105-2628-B-038-011-MY3 DOI: 10.1002/ijc.31324 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. History: Received 24 Oct 2017; Accepted 5 Feb 2018; Online 8 Mar 2018 Correspondence to: Hung-Cheng Lai, MD, PhD, No. 291, Jhongjheng Rd, Jhonghe, New Taipei 23561, Taiwan, E-mail: hclai30656@gmail. com or hclai@s.tmu.edu.tw",
year = "2018",
month = jul,
day = "15",
doi = "10.1002/ijc.31324",
language = "English (US)",
volume = "143",
pages = "355--367",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "2",
}