CREB Activation: A Gene Signature and Control Switch in Prostate Cancer
Abstract
During the first year of funding, we identified a specific set of genes elevated in PCa whose expression is predicted to be determined by the transcription factor CREB1 or ATF1. Using qRT-PCR and immunoblotting, we validated that some of these are elevated in tumor cells and not expressed in normal cells. We further demonstrated that activated CREB is specifically bound to the CREB binding elements in the promoters of GATA2 and TWIST1 in tumor cells. We generated Tet-inducible shRNA lines to knock down CREB1 and ATF1 in the tumor cells and found that CREB1 and ATF1 have opposite functions. CREB1 suppresses terminal luminal cell differentiation in tumor cells and its removal restores luminal properties. However, because CREB1 is required for luminal cell survival, they eventually die. In contrast, ATF1 is required for terminal luminal cell differentiation, and its removal from tumor cells does not restore terminal differentiation. We determined that these differences in function are related to their ability to suppress and enhance the expression of the chromatin binding protein, ING4, which is required for luminal cell differentiation and lost in tumor cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2018
- Accession Number
- AD1063941
Entities
People
- Cynthia K. Miranti
Organizations
- University of Arizona