TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target

Lin Yu Chen, Rui Lan Huang, Michael W.Y. Chan, Pearlly S. Yan, Tien Shuo Huang, Ren Chin Wu, Yohan Suryo Rahmanto, Po Hsuan Su, Yu Chun Weng, Jian Liang Chou, Tai Kuang Chao, Yu Chi Wang, Ie Ming Shih, Hung Cheng Lai*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

24 Scopus citations

Abstract

Ten-eleven translocation methylcytosine dioxygenase-1, TET1, takes part in active DNA demethylation. However, our understanding of DNA demethylation in cancer biology and its clinical significance remain limited. This study showed that TET1 expression correlated with poor survival in advanced-stage epithelial ovarian carcinoma (EOC), and with cell migration, anchorage-independent growth, cancer stemness, and tumorigenicity. In particular, TET1 was highly expressed in serous tubal intraepithelial carcinoma (STIC), a currently accepted type II EOC precursor, and inversely correlated with TP53 mutations. Moreover, TET1 could demethylate the epigenome and activate multiple oncogenic pathways, including an immunomodulation network having casein kinase II subunit alpha (CK2α) as a hub. Patients with TET1highCK2αhigh EOCs had the worst outcomes, and TET1-expressing EOCs were more sensitive to a CK2 inhibitor, both in vitro and in vivo. Our findings uncover the oncogenic and poor prognostic roles of TET1 in EOC and suggest an unexplored role of epigenetic reprogramming in early ovarian carcinogenesis. Moreover, the immunomodulator CK2α represents a promising new therapeutic target, warranting clinical trials of the tolerable CK2 inhibitor, CX4945, for precision medicine against EOC.

Original languageEnglish
Pages (from-to)363-376
Number of pages14
JournalJournal of Pathology
Volume248
Issue number3
DOIs
StatePublished - 07 2019

Bibliographical note

Publisher Copyright:
Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords

  • DNA demethylation
  • casein kinase-2
  • epigenetics
  • epithelial ovarian cancer
  • ten-eleven translocation-1

Fingerprint

Dive into the research topics of 'TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target'. Together they form a unique fingerprint.

Cite this