title: Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression.
abstract: Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that play key roles in breast cancer biology. We hypothesized that interaction of HIF-1 with epigenetic regulators may increase HIF-1 transcriptional activity, and thereby promote breast cancer progression. We report that the histone demethylase jumonji domain containing protein 2C (JMJD2C) selectively interacts with HIF-1α, but not HIF-2α, and that HIF-1α mediates recruitment of JMJD2C to the hypoxia response elements of HIF-1 target genes. JMJD2C decreases trimethylation of histone H3 at lysine 9, and enhances HIF-1 binding to hypoxia response elements, thereby activating transcription of BNIP3, LDHA, PDK1, and SLC2A1, which encode proteins that are required for metabolic reprogramming, as well as LOXL2 and L1CAM, which encode proteins that are required for lung metastasis. JMJD2C expression is significantly associated with expression of GLUT1, LDHA, PDK1, LOX, LOXL2, and L1CAM mRNA in human breast cancer biopsies. JMJD2C knockdown inhibits breast tumor growth and spontaneous metastasis to the lungs of mice following mammary fat pad injection. Taken together, these findings establish an important epigenetic mechanism that stimulates HIF-1-mediated transactivation of genes encoding proteins involved in metabolic reprogramming and lung metastasis in breast cancer.
authors.affiliation: Vascular Program, Institute for Cell Engineering, Department of Biological Chemistry, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.forename: Ryan
authors.initials: R
authors.lastname: Chang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhong
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000503:physiopathology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007553:Isotope Labeling; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D010957:Plasmids / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D051793:Hypoxia-Inducible Factor 1; C413655:KDM4C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases