The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth.
Estrogen receptor alpha (ERalpha) plays an important role in breast cancer. Upregulation of HIF-1alpha in ER(alpha)-positive cancers suggests that HIF-1alpha may cooperate with ERalpha to promote breast cancer progression and consequently affect breast cancer treatment. Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. We also show that JMJD2B and the hypoxia marker CA9 together stratify a subclass of breast cancer patients and predict a worse outcome of these breast cancers. Our findings provide a biological rationale to support the therapeutic targeting of histone demethylases in breast cancer patients.
Yang
Jun
J
Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, United Kingdom.
Jubb
Adrian M
AM
Pike
Luke
L
Buffa
Francesca M
FM
Turley
Helen
H
Baban
Dilair
D
Leek
Russell
R
Gatter
Kevin C
KC
Ragoussis
Jiannis
J
Harris
Adrian L
AL
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D018816:Genes, cdc; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human