The Role of HOX Proteins in Androgen-Independent Prostate Cancer

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 lines1. 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 various tumorigenic and non-tumorigenic prostate cell 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, our original hypothesis proposed that inhibition of these coactivators may account for the HOX-dependent suppression of androgen receptor AR-mediated transcription. However, recent data suggests that overexpression of CBP only partially relieves the inhibition of androgen receptor-mediated transcription by HOXC8. We therefore expanded our search for other cofactors potentially involved in androgen signaling, and found that SRC-3 selectively and completely restores the inhibition of androgen receptor-mediated transcription by HOXC8. In order to determine the mechanism of action of HOXC8 inhibition of androgen signaling, various immunoprecipitation experiments were performed using an LNCaP cell line stably overexpressing HOXC8.