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FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

Authors
Kang, JengminShin, Seung-HyunYoon, HaejinHuh, JuneShin, Hyun-WooChun, Yang-SookPark, Jong-Wan
Issue Date
1-3월-2018
Publisher
AMER ASSOC CANCER RESEARCH
Citation
CANCER RESEARCH, v.78, no.5, pp.1184 - 1199
Indexed
SCIE
SCOPUS
Journal Title
CANCER RESEARCH
Volume
78
Number
5
Start Page
1184
End Page
1199
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/76780
DOI
10.1158/0008-5472.CAN-17-2506
ISSN
0008-5472
Abstract
The prolyl hydroxylase domain-containing proteins (PHD-13) and the asparaginyl hydroxlyase factor inhibiting HIF (FIH) are oxygen sensors for hypoxia-inducible factor-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here, we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxia-induced cancer metastasis. Significance: These findings deepen understanding of oxygen-dependent gene regulation and cancer metastasis in response to hypoxia. (C) 2017 AACR.
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