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

doi:10.1002/path.5266

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

10 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 TET1^highCK2α^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 language	English (US)
Pages (from-to)	363-376
Number of pages	14
Journal	Journal of Pathology
Volume	248
Issue number	3
DOIs	https://doi.org/10.1002/path.5266
State	Published - Jul 2019

Keywords

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

ASJC Scopus subject areas

Pathology and Forensic Medicine

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10.1002/path.5266

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Chen, L. Y., Huang, R. L., Chan, M. W. Y., Yan, P. S., Huang, T. S., Wu, R. C., Suryo Rahmanto, Y., Su, P. H., Weng, Y. C., Chou, J. L., Chao, T. K., Wang, Y. C., Shih, I. M., & Lai, H. C. (2019). TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target. Journal of Pathology, 248(3), 363-376. https://doi.org/10.1002/path.5266

@article{4c0b5f72b5ad4a9e8550cb2b59d56493,

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

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.",

keywords = "DNA demethylation, casein kinase-2, epigenetics, epithelial ovarian cancer, ten-eleven translocation-1",

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

note = "Funding Information: The authors thank Prof. Alice Sze-Tsai Wong and Dr. Ruby Yun-Ju Huang for comments and suggestions, and Dr. Curt Balch for editing the manuscript. This work was funded by grants from the National Health Research Institutes, Taiwan (NHRI-EX104-01406BI, NHRI-EX105-01406BI, and NHRI-EX106-01406BI to HC Lai), Ministry of Science and Technology, Taiwan (MOST 105-2628-B-038-011-MY3 to HC Lai), Taipei Medical University, Taipei, Taiwan (DP2-107-21121-0-04 to HC Lai), Shuang Ho Hospital, Taipei Medical University, Taiwan (107TMU-SHH-05 to HC Lai), Graduate Student Study Abroad Program (GSSAP), National Science Council, NSC, Taiwan (NSC104-2917-1-016-002 to LY Chen), US Department of Defense, Ovarian Cancer Research Consortium grant (W81XWH-11-2-0230 to IM Shih), and The National Cancer Institute, National Institutes of Health, USA (CA215483 and CA200469 to IM Shih). Publisher Copyright: Copyright {\textcopyright} 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

year = "2019",

month = jul,

doi = "10.1002/path.5266",

language = "English (US)",

volume = "248",

pages = "363--376",

journal = "Journal of Pathology",

issn = "0022-3417",

publisher = "John Wiley and Sons Ltd",

number = "3",

}

TY - JOUR

T1 - TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target

AU - Chen, Lin Yu

AU - Huang, Rui Lan

AU - Chan, Michael W.Y.

AU - Yan, Pearlly S.

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

N1 - Funding Information: The authors thank Prof. Alice Sze-Tsai Wong and Dr. Ruby Yun-Ju Huang for comments and suggestions, and Dr. Curt Balch for editing the manuscript. This work was funded by grants from the National Health Research Institutes, Taiwan (NHRI-EX104-01406BI, NHRI-EX105-01406BI, and NHRI-EX106-01406BI to HC Lai), Ministry of Science and Technology, Taiwan (MOST 105-2628-B-038-011-MY3 to HC Lai), Taipei Medical University, Taipei, Taiwan (DP2-107-21121-0-04 to HC Lai), Shuang Ho Hospital, Taipei Medical University, Taiwan (107TMU-SHH-05 to HC Lai), Graduate Student Study Abroad Program (GSSAP), National Science Council, NSC, Taiwan (NSC104-2917-1-016-002 to LY Chen), US Department of Defense, Ovarian Cancer Research Consortium grant (W81XWH-11-2-0230 to IM Shih), and The National Cancer Institute, National Institutes of Health, USA (CA215483 and CA200469 to IM Shih). Publisher Copyright: Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PY - 2019/7

Y1 - 2019/7

N2 - 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.

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 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.

KW - DNA demethylation

KW - casein kinase-2

KW - epigenetics

KW - epithelial ovarian cancer

KW - ten-eleven translocation-1

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UR - http://www.scopus.com/inward/citedby.url?scp=85064592457&partnerID=8YFLogxK

U2 - 10.1002/path.5266

DO - 10.1002/path.5266

M3 - Article

C2 - 30883733

AN - SCOPUS:85064592457

SN - 0022-3417

VL - 248

SP - 363

EP - 376

JO - Journal of Pathology

JF - Journal of Pathology

IS - 3

ER -

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

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