Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth.
The hypoxia-inducible transcription factors (HIFs) directly and indirectly mediate cellular adaptation to reduced oxygen tensions. Recent studies have shown that the histone demethylase genes JMJD1A, JMJD2B, and JARID1B are HIF targets, suggesting that HIFs indirectly influence gene expression at the level of histone methylation under hypoxia. In this study, we identify a subset of hypoxia-inducible genes that are dependent on JMJD1A in both renal cell and colon carcinoma cell lines. JMJD1A regulates the expression of adrenomedullin (ADM) and growth and differentiation factor 15 (GDF15) under hypoxia by decreasing promoter histone methylation. In addition, we demonstrate that loss of JMJD1A is sufficient to reduce tumor growth in vivo, demonstrating that histone demethylation plays a significant role in modulating growth within the tumor microenvironment. Thus, hypoxic regulation of JMJD1A acts as a signal amplifier to facilitate hypoxic gene expression, ultimately enhancing tumor growth.
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, CA 94303-5152, USA. giaccia@stanford.edu
Adam J
AJ
Krieg
Erinn B
EB
Rankin
Denise
D
Chan
Olga
O
Razorenova
Sully
S
Fernandez
Amato J
AJ
Giaccia
D053607:Adrenomedullin / Q000096:biosynthesis; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis*; D008297:Male; D008745:Methylation; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014183:Transplantation, Heterologous
C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053607:Adrenomedullin; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human