Abstract
The prolyl hydroxylase domain-containing proteins (PHD1-3) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1184-1199 |
| Number of pages | 16 |
| Journal | Cancer Research |
| Volume | 78 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2018 Mar 1 |
Bibliographical note
Funding Information:We would like to thank Prof. Gregg L. Semenza (Johns Hopkins University School of Medicine) for scientific discussion and kind advice. J.W. Park received two grants from the National Research Foundation of Korea (2017015015 and 2017048432).
Publisher Copyright:
© 2017 American Association for Cancer Research.
ASJC Scopus subject areas
- Oncology
- Cancer Research
