Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 49, Pages E3367-E3376Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1217394109
Keywords
H3K9me3; SILAC; chromatin immunoprecipitation; gene expression
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Funding
- National Heart, Lung, and Blood Institute [N01-HV28180, HHS-N268201000032C]
- Johns Hopkins Institute for Cell Engineering
- Fowler Foundation for Advanced Research in the Medical Sciences
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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-1 alpha, but not HIF-2 alpha, and that HIF-1 alpha 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.
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