Hypoxia-induced methylation of a pontin chromatin remodeling factor

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 33; pp. 13510 - 13515
• Main Authors: Lee, Jason S., Kim, Yunho, Bhin, Jinhyuk, Shin, Hi-Jai R., Nam, Hye Jin, Lee, Seung Hoon, Yoon, Jong-Bok, Binda, Olivier, Gozani, Or, Hwang, Daehee, Baek, Sung Hee
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.08.2011; National Acad Sciences
• Subjects: Adenosinetriphosphatase; Anaerobic conditions; Antibodies; ATPases Associated with Diverse Cellular Activities; Biological Sciences; Cancer; Carrier Proteins - metabolism; Cell Hypoxia; Cell Line, Tumor; Cell motility; Chromatin; Chromatin - genetics; Chromatin Assembly and Disassembly; Chromatin remodeling; Data processing; Deoxyribonucleic acid; DNA; DNA helicase; DNA Helicases - metabolism; DNA methylation; Epigenomics; Ets-1 protein; Gene expression regulation; Genes; HEK293 cells; Histones; Humans; Hypoxia; Hypoxia-inducible factor 1 alpha; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Metastases; Metastasis; Methylation; Methyltransferase; Methyltransferases - metabolism; Neoplasm Proteins - metabolism; Promoters; Recruitment; Stem cells; Transcription; Transcription, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1106106108

Pontin is a chromatin remodeling factor that possesses both ATPase and DNA helicase activities. Although Pontin is frequently overexpressed in human cancers of various types and implicated in oncogenic functions, the upstream signaling network leading to the regulation of Pontin that in turn affects transcription of downstream target genes has not been extensively studied. Here, we identify Pontin is methylated by G9a/GLP methyltransferases in hypoxic condition and potentiates HIF-1α-mediated activation by increasing the recruitment of p300 coactivator to a subset of HIF-1α target promoters. Intriguingly, Pontin methylation results in the increased invasive and migratory properties by activating downstream target gene, Ets1. In contrast, inhibition of Pontin methylation results in the suppression of tumorigenic and metastatic properties. Together, our data provide new approaches by targeting Pontin methylation and its downstream targets for the development of therapeutic agents for human cancers.