Epigenetic loss of heparan sulfate 3-O-sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis

Rui Lan Huang, Hsiang Ju Chen, Lin Yu Chen, Tai Kuang Chao, Wei Yu Lin, Phui Ly Liew, Po Hsuan Su, Yu Chun Weng, Yu Chi Wang, Chi Chun Liao, Yaw Wen Hsu, Hui Chen Wang, Hung Cheng Lai

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Abstract

Precision medicine requires markers for therapeutic guidance. The purpose of this study was to determine whether epithelial ovarian cancer (EOC) epigenetics can lead to the identification of biomarkers for precision medicine. Through integrative methylomics, we discovered and validated the epigenetic signature of NEFH and HS3ST2 as an independent prognostic factor for type II EOC in our dataset (n = 84), and two independent methylomics datasets (total n = 467). Integrated transcriptomics dataset (n = 1147) and tissue microarrays (n = 54) of HS3ST2 also related to high-methylation statuses and the EOC prognosis. Mechanistic explorations of HS3ST2 have assessed responses to oncogenic stimulations such as IL-6, EGF, and FGF2 in cancer cells. The combination of HS3ST2 and various oncogenic ligands also confers the worse outcome. 3-O-sulfation of heparan sulfate by HS3ST2 makes ovarian cancer cells intrinsically sensitive to oncogenic signals, which sheds new light on the application of HS3ST2 as a companion diagnostic for targeted therapy using kinase inhibitors or therapeutic antibodies.

Original languageEnglish
Pages (from-to)1943-1953
Number of pages11
JournalInternational Journal of Cancer
Volume143
Issue number8
DOIs
Publication statusPublished - Oct 15 2018

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Keywords

  • DNA methylation
  • epithelial ovarian cancer
  • heparan sulfation
  • HS3ST2
  • prognosis
  • targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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