EPAS1 increases SDHA to inhibit proliferation of multiple myeloma cells by restoring TCA Cycle.

Multiple myeloma (MM) is a hematologic malignancy characterized by monoclonal proliferation of plasma cells. As most patients with MM relapse after multiple lines of therapy, seeking new treatment strategies is an urgent task for current research. We found succinate dehydrogenase subunit A (SDHA) was closely related to prognosis of MM patients. SDHA promoted the tricarboxylic acid (TCA) cycle and inhibited glycolysis. It subsequently repressed the proliferation and invasion of MM both in vitro and in vivo. Endothelial pAS domain protein1 (EPAS1), also known as hypoxia-inducible factor-2α (HIF-2α), is a key transcription factor in response to hypoxia. We found that patients with high EPAS1 expression had a better prognosis. EPAS1 promoted the TCA cycle, suppressed glycolysis, and inhibited the proliferation and invasion of MM both in vitro and in vivo. EPAS1 enhanced SDHA expression by inhibiting HDAC2 mRNA expression and increasing acetylation at the SDHA histone H3K27 site. In conclusion, activating the EPAS1-HDAC2-SDHA axis could restore the TCA cycle as the dominant glucose metabolism pathway in order to inhibit proliferation of MM cells.