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

In soft tissue sarcomas (STS), low intratumoural O-2 (hypoxia) is a poor prognostic indicator. HIF-1 alpha mediates key transcriptional responses to hypoxia, and promotes STS metastasis; however, the role of the related HIF-2 alpha protein is unknown. Surprisingly, here we show that HIF-2 alpha inhibits high-grade STS cell growth in vivo, as loss of HIF-2 alpha 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-2 alpha) 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-2 alpha, but not HIF-1 alpha, accumulation in multiple STS subtypes. Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2 alpha deletion, implicating HIF-2 alpha as a biomarker for Vorinostat efficacy in STS.