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 language | English (US) |
|---|---|
| Pages (from-to) | 209-221 |
| Number of pages | 13 |
| Journal | Cell reports |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - Oct 6 2015 |
Funding
We thank Dr. Ximing J. Yang (Northwestern University) for assistance on RNA ISH and Dr. Nicholas Erho (GenomeDx Biosciences) for data mining. Tissue microarrays were provided by the Northwestern University prostate cancer SPORE (P50 CA090386). J.K. and Y.A.Y were supported by the NIH T32 CA080621 and T32 CA09560 , respectively. This work was supported in part by the NIH R01CA172384 (to J.Y.), U.S. Department of Defense W81XWH-14-1-0023 (to J.Y.), and the Research Scholar Award RSG-12-085-01 (to J.Y.) from the American Cancer Society .
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
