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

Research output: Contribution to journalArticle

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 TET1 high CK2α high 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 (US)
JournalJournal of Pathology
DOIs
StatePublished - Jan 1 2019

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Casein Kinase II
Carcinoma
Dioxygenases
Precision Medicine
Immunomodulation
DNA
Carcinoma in Situ
Immunologic Factors
Therapeutics
Epigenomics
Cell Movement
Neoplasms
Carcinogenesis
Clinical Trials
Mutation
Survival
Ovarian epithelial cancer
Growth

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target. / Chen, Lin Yu; Huang, Rui Lan; Chan, Michael W.Y.; Yan, Pearlly S.; Huang, Tien Shuo; Wu, Ren Chin; Suryo Rahmanto, Yohan; Su, Po Hsuan; Weng, Yu Chun; Chou, Jian Liang; Chao, Tai Kuang; Wang, Yu Chi; Shih, Ie Ming; Lai, Hung Cheng.

In: Journal of Pathology, 01.01.2019.

Research output: Contribution to journalArticle

Chen, LY, Huang, RL, Chan, MWY, Yan, PS, Huang, TS, Wu, RC, Suryo Rahmanto, Y, Su, PH, Weng, YC, Chou, JL, Chao, TK, Wang, YC, Shih, IM & Lai, HC 2019, 'TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target', Journal of Pathology. https://doi.org/10.1002/path.5266
Chen, Lin Yu ; Huang, Rui Lan ; Chan, Michael W.Y. ; Yan, Pearlly S. ; Huang, Tien Shuo ; Wu, Ren Chin ; Suryo Rahmanto, Yohan ; Su, Po Hsuan ; Weng, Yu Chun ; Chou, Jian Liang ; Chao, Tai Kuang ; Wang, Yu Chi ; Shih, Ie Ming ; Lai, Hung Cheng. / TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target. In: Journal of Pathology. 2019.
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AU - Huang, Tien Shuo

AU - Wu, Ren Chin

AU - Suryo Rahmanto, Yohan

AU - Su, Po Hsuan

AU - Weng, Yu Chun

AU - Chou, Jian Liang

AU - Chao, Tai Kuang

AU - Wang, Yu Chi

AU - Shih, Ie Ming

AU - Lai, Hung Cheng

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AB - 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 TET1 high CK2α high 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.

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