PMID- 29860315
OWN - NLM
STAT- MEDLINE
DCOM- 20190805
LR  - 20190918
IS  - 1362-4962 (Electronic)
IS  - 0305-1048 (Print)
IS  - 0305-1048 (Linking)
VI  - 46
IP  - 13
DP  - 2018 Jul 27
TI  - Methylation of hypoxia-inducible factor (HIF)-1alpha by G9a/GLP inhibits HIF-1 
      transcriptional activity and cell migration.
PG  - 6576-6591
LID - 10.1093/nar/gky449 [doi]
AB  - 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 alpha subunit of HIF-1 (HIF-1alpha) and catalyzed mono- and di-methylation of HIF-1alpha 
      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-1alpha transactivation domain 
      function but not increased HIF-1alpha 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.
FAU - Bao, Lei
AU  - Bao L
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
FAU - Chen, Yan
AU  - Chen Y
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
FAU - Lai, Hsien-Tsung
AU  - Lai HT
AD  - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 
      75390, USA.
FAU - Wu, Shwu-Yuan
AU  - Wu SY
AD  - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 
      75390, USA.
AD  - Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, 
      USA.
FAU - Wang, Jennifer E
AU  - Wang JE
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
FAU - Hatanpaa, Kimmo J
AU  - Hatanpaa KJ
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
FAU - Raisanen, Jack M
AU  - Raisanen JM
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
FAU - Fontenot, Miles
AU  - Fontenot M
AD  - Medical Scientist Training Program, UT Southwestern Medical Center, Dallas, TX 
      75390, USA.
FAU - Lega, Bradley
AU  - Lega B
AD  - Department of Neurological Surgery, UT Southwestern Medical Center, Dallas, TX 
      75390, USA.
FAU - Chiang, Cheng-Ming
AU  - Chiang CM
AD  - Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 
      75390, USA.
AD  - Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, 
      USA.
AD  - Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, 
      USA.
FAU - Semenza, Gregg L
AU  - Semenza GL
AD  - Vascular Program, The Johns Hopkins Institute for Cell Engineering, Baltimore, MD 
      21205, USA.
FAU - Wang, Yingfei
AU  - Wang Y
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
AD  - Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, 
      Dallas, TX 75390, USA.
FAU - Luo, Weibo
AU  - Luo W
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
AD  - Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, 
      USA.
LA  - eng
GR  - R00 CA168746/CA/NCI NIH HHS/United States
GR  - R00 NS078049/NS/NINDS NIH HHS/United States
GR  - R01 CA103867/CA/NCI NIH HHS/United States
GR  - R35 GM124693/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nucleic Acids Res
JT  - Nucleic acids research
JID - 0411011
RN  - 0 (Autoantigens)
RN  - 0 (GOLGA6A protein, human)
RN  - 0 (Golgi Matrix Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Histocompatibility Antigens)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 2.1.1.43 (EHMT2 protein, human)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - K3Z4F929H6 (Lysine)
MH  - Autoantigens/*metabolism
MH  - Cell Hypoxia
MH  - Cell Line
MH  - Cell Movement
MH  - *Epigenesis, Genetic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Glioblastoma/*genetics/metabolism/physiopathology
MH  - Golgi Matrix Proteins/*metabolism
MH  - Histocompatibility Antigens/*metabolism
MH  - Histone-Lysine N-Methyltransferase/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & 
      inhibitors/chemistry/*metabolism
MH  - Lysine/metabolism
MH  - Methylation
MH  - Response Elements
MH  - *Transcription, Genetic
PMC - PMC6061882
EDAT- 2018/06/04 06:00
MHDA- 2019/08/06 06:00
PMCR- 2018/05/31
CRDT- 2018/06/04 06:00
PHST- 2017/10/03 00:00 [received]
PHST- 2018/05/09 00:00 [accepted]
PHST- 2018/06/04 06:00 [pubmed]
PHST- 2019/08/06 06:00 [medline]
PHST- 2018/06/04 06:00 [entrez]
PHST- 2018/05/31 00:00 [pmc-release]
AID - 5025897 [pii]
AID - gky449 [pii]
AID - 10.1093/nar/gky449 [doi]
PST - ppublish
SO  - Nucleic Acids Res. 2018 Jul 27;46(13):6576-6591. doi: 10.1093/nar/gky449.