LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer

• DOI: 10.1016/j.celrep.2015.08.069
• Publication Date: 2015-09-24T22:16:58Z
• Authors: Ali Zhang; Jonathan C. Zhao; Jung Kim; Ka-wing Fong; Yeqing Angela Yang; Debabrata Chakrav...; Yin-Yuan Mo; Jindan Yu
• Keywords: Male; Chromatin Immunoprecipitation; Proteasome Endopeptidase Complex; QH301-705.5; Cell Survival; Article; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Humans; Biology (General); In Situ Hybridization; Cell Proliferation; 0303 health sciences; Binding Sites; Prostate; Proto-Oncogene Proteins c-mdm2; 3. Good health; Gene Expression Regulation, Neoplastic; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Proteolysis; Androgens; RNA, Long Noncoding; Protein Binding; Signal Transduction

Understanding the mechanisms of androgen receptor (AR) activation in the milieu of low androgen is critical to effective treatment of castration-resistant prostate cancer (CRPC). Here, we report HOTAIR as an androgen-repressed lncRNA, and, as such, it is markedly upregulated following androgen deprivation therapies and in CRPC. We further demonstrate a distinct mode of lncRNA-mediated gene regulation, wherein HOTAIR binds to the AR protein to block its interaction with the E3 ubiquitin ligase MDM2, thereby preventing AR ubiquitination and protein degradation. Consequently, HOTAIR expression is sufficient to induce androgen-independent AR activation and drive the AR-mediated transcriptional program in the absence of androgen. Functionally, HOTAIR overexpression increases, whereas HOTAIR knockdown decreases, prostate cancer cell growth and invasion. Taken together, our results provide compelling evidence of lncRNAs as drivers of androgen-independent AR activity and CRPC progression, and they support the potential of lncRNAs as therapeutic targets.