Soft tissue sarcomas (STS) are a group of malignancies that arise from mesenchymal tissue, consisting of over 50 distinct histiologic subtypes. Unfortunately, the five-year survival rate of sarcoma patients has remained relatively unchanged, and due to the rarity of the disease, research and development of adequate therapeutics for STS lags behind other cancers. Therefore, understanding the molecular drivers of STS is important in developing new therapeutics, as well as discovering druggable processes that occur across multiple subtypes. One feature common to STS is hypoxia, or low O2 conditions. Using molecular biology, biochemical approaches, genetically engineered mouse models, as well as querying publically available data sets, we determined that Hypoxia Inducible Factor (HIF)-2α suppresses fibrosarcoma, dedifferentiated liposarcoma, and undifferentiated pleomorphic sarcoma (UPS) growth in vivo. In addition, we found that STS patient samples express low levels of EPAS1 (the gene encoding HIF-2α). Our results showed increased levels of the calcium activated chloride channel ANO1, in HIF-2α deficient UPS tumors, which increased mTORC1 activity. Additionally, we determined that HIF-2α was epigenetically silenced in STS, and could be re-expressed with histone deacetylation inhibitor (HDACi) treatment. HDACi suppressed STS growth in vivo in a HIF-2α dependent manner. Moreover, we established that autophagy promotes fibrosarcoma and UPS survival under hypoxic and ischemic-like conditions. Autophagic inhibition, either with chloroquine or the more potent autophagy inhibitor Lys05, reduces UPS and fibrosarcoma growth in vitro and in vivo. From these studies, future clinical studies are warranted to test histone deacetylase inhibitors and autophagy inhibitors in patients with the STS subtypes examined here.