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

doi:10.1002/ijc.31580

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

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

12 Citations (Scopus)

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 language	English
Pages (from-to)	1943-1953
Number of pages	11
Journal	International Journal of Cancer
Volume	143
Issue number	8
DOIs	https://doi.org/10.1002/ijc.31580
Publication status	Published - Oct 15 2018

Keywords

DNA methylation
epithelial ovarian cancer
heparan sulfation
HS3ST2
prognosis
targeted therapy

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ijc.31580

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Huang, R. L., Chen, H. J., Chen, L. Y., Chao, T. K., Lin, W. Y., Liew, P. L., Su, P. H., Weng, Y. C., Wang, Y. C., Liao, C. C., Hsu, Y. W., Wang, H. C., & Lai, H. C. (2018). Epigenetic loss of heparan sulfate 3-O-sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis. International Journal of Cancer, 143(8), 1943-1953. https://doi.org/10.1002/ijc.31580

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

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.",

keywords = "DNA methylation, epithelial ovarian cancer, heparan sulfation, HS3ST2, prognosis, targeted therapy",

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

note = "Funding Information: We thank Tien-Shuo Huang for technical support. Conflict of interest: The authors declare no competing financial interests. Author Contributions: R.L.H. performed clinical experiments, wrote the manuscript and analyzed data. H.J.C. planned and performed the experiments for in vitro studies. L.Y.C. helped with in vitro studies. Y.W.H. helped with discussion and western blotting experiments. T.K.C. and P.L.L. performed and managed the histopathological and immunochemical analysis. W.Y.L. helped with the data analysis. P.H.S. helped with in vitro studies design. Yu-Chun W. helped with in vitro studies. Yu-Chi W. and C.C.L. reviewed the clinical evaluations. H.C.W. helped with DNA preparation and bisulfite pyrosequencing. H.C.L. initiated the study, formulated the hypothesis and wrote the manuscript. Publisher Copyright: {\textcopyright} 2018 UICC",

year = "2018",

month = oct,

day = "15",

doi = "10.1002/ijc.31580",

language = "English",

volume = "143",

pages = "1943--1953",

journal = "International Journal of Cancer",

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T1 - Epigenetic loss of heparan sulfate 3-O-sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis

AU - Huang, Rui Lan

AU - Chen, Hsiang Ju

AU - Chen, Lin Yu

AU - Chao, Tai Kuang

AU - Lin, Wei Yu

AU - Liew, Phui Ly

AU - Su, Po Hsuan

AU - Weng, Yu Chun

AU - Wang, Yu Chi

AU - Liao, Chi Chun

AU - Hsu, Yaw Wen

AU - Wang, Hui Chen

AU - Lai, Hung Cheng

N1 - Funding Information: We thank Tien-Shuo Huang for technical support. Conflict of interest: The authors declare no competing financial interests. Author Contributions: R.L.H. performed clinical experiments, wrote the manuscript and analyzed data. H.J.C. planned and performed the experiments for in vitro studies. L.Y.C. helped with in vitro studies. Y.W.H. helped with discussion and western blotting experiments. T.K.C. and P.L.L. performed and managed the histopathological and immunochemical analysis. W.Y.L. helped with the data analysis. P.H.S. helped with in vitro studies design. Yu-Chun W. helped with in vitro studies. Yu-Chi W. and C.C.L. reviewed the clinical evaluations. H.C.W. helped with DNA preparation and bisulfite pyrosequencing. H.C.L. initiated the study, formulated the hypothesis and wrote the manuscript. Publisher Copyright: © 2018 UICC

PY - 2018/10/15

Y1 - 2018/10/15

N2 - 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.

AB - 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.

KW - DNA methylation

KW - epithelial ovarian cancer

KW - heparan sulfation

KW - HS3ST2

KW - prognosis

KW - targeted therapy

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DO - 10.1002/ijc.31580

M3 - Article

AN - SCOPUS:85052896722

SN - 0020-7136

VL - 143

SP - 1943

EP - 1953

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 8

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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