CREB Activation: A Gene Signature and Control Switch in Prostate Cancer
Abstract
The primary hypothesis of this project was to test whether aberrant temporal CREB1 activation, due to PTEN loss, prior to full luminal cell commitment, promotes a prostate cancer oncogenic program that is associated with poor outcomes in patients. The goals were to 1) determine the role of CREB1 in differentiation and oncogenesis; 2) identify the CREB1 targets necessary for prostate cancer oncogenesis; and 3) define the CREB1 signature in clinical human prostate cancer samples. These studies uniquely revealed that there is a specific set of genes elevated in PCa whose expression is controlled by the transcription factor CREB1. We found that CREB1 suppresses terminal cell differentiation in the luminal tumor cells by suppressing expression of the chromatin binding protein, ING4 required for normal luminal cell differentiation. The mechanisms include transcriptional suppression as well as upregulation of an ING4 E3 ligase, JFK. Loss of CREB1 rescues differentiation and suppresses oncogenesis. Several CREB1 targets, GATA2, Twist1, CAMK2B, and Jag1 were identified and validated, and preliminary data indicate these are in part responsible for the tumor phenotypes mediated by CREB1. Human tissue studies revealed that ING4 loss, a target of CREB1, is negatively correlated with Erg fusion and positively correlated with PTEN loss, providing insight into the subclasses of tumors where CREB1 might be most active.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2021
- Accession Number
- AD1208067
Entities
People
- Cynthia K. Miranti
Organizations
- University of Arizona