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

Ali Zhang, Jonathan C. Zhao, Jung Kim, Ka wing Fong, Yeqing Angela Yang, Debabrata Chakravarti, Yin Yuan Mo, Jindan Yu*

*Corresponding author for this work

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)209-221
Number of pages13
JournalCell reports
Volume13
Issue number1
DOIs
StatePublished - Oct 6 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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