CtBP determines ovarian cancer cell fate through repression of death receptors
Abstract
C-terminal binding protein 2 (CtBP2) is elevated in epithelial ovarian cancer, especially in the aggressive and highly lethal subtype, high-grade serous ovarian cancer (HGSOC). However, whether HGSOC tumor progression is dependent on CtBP2 or its paralog CtBP1, is not well understood. Here we report that CtBP1/2 repress HGSOC cell apoptosis through silencing of death receptors (DRs) 4/5. CtBP1 or 2 knockdown upregulated DR4/5 expression, and triggered autonomous apoptosis via caspase 8 activation, but dependent on cell-type context. Activation of DR4/5 by CtBP1/2 loss also sensitized HGSOC cell susceptibility to the proapoptotic DR4/5 ligand TRAIL. Consistent with its function as transcription corepressor, CtBP1/2 bound to the promoter regions of DR4/5 and repressed DR4/5 expression, presumably through recruitment to a repressive transcription regulatory complex. We also found that CtBP1 and 2 were both required for repression of DR4/5. Collectively, this study identifies CtBP1 and 2 as potent repressors of DR4/5 expression and activity, and supports the targeting of CtBP as a promising therapeutic strategy for HGSOC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 24, 2020
- Source ID
- 10.1038/s41419-020-2455-7
Entities
People
- Boxiao Ding
- Larisa Litovchick
- Priyadarshan K Damle
- Ronny Drapkin
- Steven R. Grossman
- Yuan Fang
Organizations
- Adelson Foundation
- National Cancer Institute
- United States Department of Defense
- United States Department of Health and Human Services