Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth

Michael S. Nakazawa, T. S. Karin Eisinger-Mathason, Navid Sadri, Joshua D. Ochocki, Terence P. F. Gade, Ruchi K. Amin and M. Celeste Simon ()
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Michael S. Nakazawa: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA
T. S. Karin Eisinger-Mathason: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA
Navid Sadri: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA
Joshua D. Ochocki: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA
Terence P. F. Gade: Perelman School of Medicine at the University of Pennsylvania
Ruchi K. Amin: Howard Hughes Medical Institute
M. Celeste Simon: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III Room 456, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract In soft tissue sarcomas (STS), low intratumoural O2 (hypoxia) is a poor prognostic indicator. HIF-1α mediates key transcriptional responses to hypoxia, and promotes STS metastasis; however, the role of the related HIF-2α protein is unknown. Surprisingly, here we show that HIF-2α inhibits high-grade STS cell growth in vivo, as loss of HIF-2α promotes sarcoma proliferation and increases calcium and mTORC1 signalling in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. We find that most human STS have lower levels of EPAS1 (the gene encoding HIF-2α) expression relative to normal tissue. Many cancers, including STS, contain altered epigenetics, and our findings define an epigenetic mechanism whereby EPAS1 is silenced during sarcoma progression. The clinically approved HDAC inhibitor Vorinostat specifically increases HIF-2α, but not HIF-1α, accumulation in multiple STS subtypes. Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2α deletion, implicating HIF-2α as a biomarker for Vorinostat efficacy in STS.

Date: 2016
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DOI: 10.1038/ncomms10539

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