The Role of HOX Proteins in Androgen-Independent Prostate Cancer
Abstract
HOX genes encode a large family of transcription factors involved in key developmental decisions, and are often aberrantly expressed in cancer. Our laboratory has previously shown that a subset of genes of the HOXC cluster are overexpressed in primary prostate tumors, metastases, and prostate cancer (PCa) cell lines. Increasing transient expression of HOXC8 in LNCaP PCa cells as well as HPr-1 AR non-tumorigenic prostate epithelial cells results in a progressive suppression of androgen responsive promoters. Transcription from both the mouse probasin promoter and the MMTV promoter is inhibited at levels of HOXC8 expression comparable to those seen in PCa cell lines. Other members of the HOX family also inhibit androgen signaling. We have created LNCaP and HPr-1 AR derived lines that stably overexpress HOXC8 and show that signaling through androgen responsive promoters is inhibited, and PSA mRNA levels are decreased in these cell lines. HOX proteins block the histone acetyltransferase activity of the coactivators CBP and p3002. As these are key mediators of steroid-dependent transcription, inhibition of these coactivators could account for the HOX-dependent suppression of androgen receptor-mediated transcription. We show that overexpression of CBP relieves the inhibition of androgen receptor-mediated transcription by HOXC8. Further, chromatin immunoprecipitation demonstrates that HOXC8 expression inhibits hormone-induced histone acetylation at MMTV. HOXC8 overexpression has been shown to correlate with higher Gleason grade PCa3. Our preliminary studies demonstrate that stable overexpression of HOXC8 increases HPr-1 AR invasiveness in vitro. In contrast to androgens, the secosteroid vitamin D has been shown to have antiproliferative, prodifferentiation and antimetastatic properties in PCa. Increasing expression of HOXC8 also results in a progressive suppression of vitamin D-induced transcription in vitamin D-responsive ALVA-31 PCa cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2007
- Accession Number
- ADA479291
Entities
People
- Sunshine Daddario
Organizations
- University of Colorado Boulder