| First Author | Nakazawa MS | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 10539 | PubMed ID | 26837714 |
| Mgi Jnum | J:236284 | Mgi Id | MGI:5805622 |
| Doi | 10.1038/ncomms10539 | Citation | Nakazawa MS, et al. (2016) Epigenetic re-expression of HIF-2alpha suppresses soft tissue sarcoma growth. Nat Commun 7:10539 |
| abstractText | In soft tissue sarcomas (STS), low intratumoural O2 (hypoxia) is a poor prognostic indicator. HIF-1alpha mediates key transcriptional responses to hypoxia, and promotes STS metastasis; however, the role of the related HIF-2alpha protein is unknown. Surprisingly, here we show that HIF-2alpha inhibits high-grade STS cell growth in vivo, as loss of HIF-2alpha 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-2alpha) 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-2alpha, but not HIF-1alpha, accumulation in multiple STS subtypes. Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2alpha deletion, implicating HIF-2alpha as a biomarker for Vorinostat efficacy in STS. |
