Previously, we have used an integrated approach to use genome-scale screening in RNAi and CRISPR-Cas9 to identify several putative cancer dependencies. From these putative dependencies, we discovered EGLN1 was a significant and selective dependency in ovarian cancer and EGLN1 dependency was further enriched in clear-cell ovarian cancers. Genetic knockout and small-molecule inhibition of EGLN1 reduced cell proliferation and increased apoptosis in vitro and in vivo. We found the function of EGLN1 as a cancer dependency is through its canonical role as a negative HIF1A regulator and knockout of HIF1A, but not HIF2A, rescues genetic knockout and small-molecule inhibition of EGLN1. Genetic and small-molecule suppression of VHL, downstream of EGLN1 in the degradation of HIF1A, similarly reduces proliferation and increases apoptosis, and is rescued by HIF1A knockout. Further, we found that forced expression of a mutated HIF1A that blocks EGLN1-dependent hydroxylation reduces proliferation and promotes apoptosis. Using RNA-sequencing, we identified several putative downstream targets of HIF1A and confirmed that HIF1A directly binds and drives transcription of negative MYC regulator MXI1. Further, we found that knockout of MXI1 reduced the effects of EGLN1-mediated suppression, indicating HIF1A-driven MYC suppression as one mechanism underlying EGLN1 dependency. Further understanding of HIF1A-mediated suppression of ovarian cancer progression will be critical to potential small-molecule therapy.
Citation Format: Colles Price, Stanley Gill, Zandra V. Ho, Shawn M. Davidson, Erin Merkel, James M. McFarland, Lisa Leung, Andrew Tang, Maria Kost-Alimova, Aviad Tsherniak, Oliver Jonas, Francisca Vazquez, William C. Hahn. Understanding HIF1A-mediated therapy in clear cell ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A67.