ING4 Loss in Prostate Cancer Progression
Abstract
The goal of this project is to identify specific differentiation events controlled by ING4, whose disruption by combined Myc/PTEN loss leads to aggressive PCa. Our three Aims are to 1) determine how ING4 controls prostate epithelial differentiation, 2) determine how loss ofING4 impacts tumorigenesis, and 3) determine how loss of ING4 in patients relates to tumor progression. To date we have published 4papers as a result of these studies that address these aims. In those papers we demonstrate: 1) ING4, downstream of Myc is required for luminal cell differentiation, ING4 loss is required for Myc-dependent oncogenesis, and ING4 expression is lost in ~60 of primary PCa tumors. This is the first time ING4 has been linked to differentiation and its loss reported in prostate cancer. 2) Myc, via p38-MAPK, drives luminal cell differentiation by inducing Notch3 mRNA transcription and stability. This is the first study to demonstrate the importance and mechanisms of Notch3 induction in luminal cell differentiation. 3) Miz1, which is absent in tumor cells, is an ING4 target that is required to suppress integrin a6b1 in normal luminal cells, which explains how integrin a6b1 can be retained in tumor cells when ING4/Miz1 is lost. 4) We developed more robust Tet-inducible shRNA vectors, which are available to the entire research community. Additional major findings not yet published include 1) JFK, an E3-ligase for ING4, is transcriptionally controlled by ING4 itself, 2) PTEN sets the timing for ING4expression and 3) ING4 loss is highly correlated with PTEN loss and Gleason grade in human tissues.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2018
- Accession Number
- AD1064681
Entities
People
- Cynthia Miranti
Organizations
- University of Arizona