Role of C-Terminal Binding Protein as Oncogene and Therapeutic Target in Epithelial Ovarian Cancer
Abstract
The C-terminal binding protein (CtBP) is elevated in epithelial ovarian cancer, especially in high-grade serous ovarian cancer (HGSOC), and has been implicated in solid tumor oncogenesis. However, the CtBP dependency in HGSOC, and thus its validity as a therapeutic target, is not well documented. Here we report that CtBP represses HGSOC apoptosis through death receptors (DRs) 4/5. We further demonstrate that CtBP represses DR4 or/and DR5 in different cell-type contexts. As a transcription corepressor, CtBP binds to the promoter regions of DR4/5, repressing DR4/5 expression, presumably through the recruitment of a repressor complex. This study identifies CtBP as a potent suppressor of DR4/5 and indicates targeting CtBP is a promising therapeutic strategy for HGSOC. We have generated tet-inducible CtBP1/2 shRNA and transduced the luciferase gene into HGSOC cell lines in preparation for orthotopic xenograft experiments. Slides and tissue microarrays were prepared of both HGSOC cases and pre-neoplastic lesions from risk-reducing surgeries in preparation for FISH as well as IHC analyses. In preparation for testing an anti-CtBP therapeutic in orthotopic xenografts, A2780 cells were treated with anti-CtBP drug 4-Cl-HIPP, which resulted in robust growth inhibition at higher concentrations. A native transgenic Pax8-Cre/CAG-LSL-CtBP2 mouse model for overexpression of CtBP2 in the fallopian tube has been developed.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2021
- Accession Number
- AD1172214
Entities
People
- Boxiao Ding
- Dipankar Bandyopadhyay
- Jolene Windle
- Keith C. Ellis
- Larisa Litovchick
- Ronny Drapkin
- Steven R. Grossman
- Yuan Fang
Organizations
- Virginia Commonwealth University