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FIH is an oxygen sensor for G9a/GLP‐driven epigenetic regulation of metastasis‐related genes in ovarian cancer
Author(s) -
KANG JENGMIN,
Park JongWan
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.524.1
Subject(s) - epigenetics , metastasis , ovarian cancer , transcription factor , cancer research , biology , hypoxia (environmental) , regulator , gene , cancer , genetics , chemistry , oxygen , organic chemistry
The dioxygenases PHD1‐3 and FIH are the oxygen sensors for hypoxia‐inducible factor (HIF)‐driven transcription of hypoxia‐induced genes. However, little is known about the oxygen sensors responsible for oxygen‐dependent epigenetic regulation. We here show that FIH plays additional roles as an oxygen sensor in G9a‐ and GLP‐driven epigenetic regulation. FIH hydroxylates and inhibits G9a and GLP under normoxia. When the FIH reaction is limited under hypoxia, G9a and GLP are activated and repress the metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. FIH and G9a expressions are reciprocally associated with clinical outcomes of ovarian cancer. Mutations of FIH‐target motifs in G9a and GLP were identified in human cancers, and they exhibit excessive H3K9 methylation and facilitate 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. Support or Funding Information This work was supported by a grant from the National Research Foundation of Korea (2017R1A4A1015015 and 2016R1A2A1A05005082 to J.W.P). Kang J received a scholarship from the BK21‐plus education program provided by the National Research Foundation of Korea. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .