Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration

Lei Bao, Yan Chen, Hsien Tsung Lai, Shwu Yuan Wu, Jennifer E. Wang, Kimmo J. Hatanpaa, Jack M. Raisanen, Miles Fontenot, Bradley Lega, Cheng Ming Chiang, Gregg L Semenza, Yingfei Wang, Weibo Luo

Research output: Contribution to journalArticle

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator in response to hypoxia and its transcriptional activity is crucial for cancer cell mobility. Here we present evidence for a novel epigenetic mechanism that regulates HIF-1 transcriptional activity and HIF-1-dependent migration of glioblastoma cells. The lysine methyltransferases G9a and GLP directly bound to the subunit of HIF-1 (HIF-1) and catalyzed mono- and di-methylation of HIF-1 at lysine (K) 674 in vitro and in vivo. K674 methylation suppressed HIF-1 transcriptional activity and expression of its downstream target genes PTGS1, NDNF, SLC6A3, and Linc01132 in human glioblastoma U251MG cells. Inhibition of HIF-1 by K674 methylation is due to reduced HIF-1 transactivation domain function but not increased HIF-1 protein degradation or impaired binding of HIF-1 to hypoxia response elements. K674 methylation significantly decreased HIF-1-dependent migration of U251MG cells under hypoxia. Importantly, we found that G9a was downregulated by hypoxia in glioblastoma, which was inversely correlated with PTGS1 expression and survival of patients with glioblastoma. Therefore, our findings uncover a hypoxia-induced negative feedback mechanism that maintains high activity of HIF-1 and cell mobility in human glioblastoma.

Original languageEnglish (US)
Pages (from-to)6576-6591
Number of pages16
JournalNucleic Acids Research
Volume46
Issue number13
DOIs
StatePublished - Jan 1 2018

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Hypoxia-Inducible Factor 1
Methylation
Cell Movement
Glioblastoma
Lysine
Cell Hypoxia
Methyltransferases
Response Elements
Epigenomics
Transcriptional Activation
Proteolysis

ASJC Scopus subject areas

  • Genetics

Cite this

Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration. / Bao, Lei; Chen, Yan; Lai, Hsien Tsung; Wu, Shwu Yuan; Wang, Jennifer E.; Hatanpaa, Kimmo J.; Raisanen, Jack M.; Fontenot, Miles; Lega, Bradley; Chiang, Cheng Ming; Semenza, Gregg L; Wang, Yingfei; Luo, Weibo.

In: Nucleic Acids Research, Vol. 46, No. 13, 01.01.2018, p. 6576-6591.

Research output: Contribution to journalArticle

Bao, L, Chen, Y, Lai, HT, Wu, SY, Wang, JE, Hatanpaa, KJ, Raisanen, JM, Fontenot, M, Lega, B, Chiang, CM, Semenza, GL, Wang, Y & Luo, W 2018, 'Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration', Nucleic Acids Research, vol. 46, no. 13, pp. 6576-6591. https://doi.org/10.1093/nar/gky449
Bao, Lei ; Chen, Yan ; Lai, Hsien Tsung ; Wu, Shwu Yuan ; Wang, Jennifer E. ; Hatanpaa, Kimmo J. ; Raisanen, Jack M. ; Fontenot, Miles ; Lega, Bradley ; Chiang, Cheng Ming ; Semenza, Gregg L ; Wang, Yingfei ; Luo, Weibo. / Methylation of hypoxia-inducible factor (HIF)-1α by G9a/GLP inhibits HIF-1 transcriptional activity and cell migration. In: Nucleic Acids Research. 2018 ; Vol. 46, No. 13. pp. 6576-6591.
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