TY - JOUR
T1 - LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer
AU - Zhang, Ali
AU - Zhao, Jonathan C.
AU - Kim, Jung
AU - Fong, Ka wing
AU - Yang, Yeqing Angela
AU - Chakravarti, Debabrata
AU - Mo, Yin Yuan
AU - Yu, Jindan
N1 - Funding Information:
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 .
Publisher Copyright:
© 2015 The Authors.
PY - 2015/10/6
Y1 - 2015/10/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2015.08.069
DO - 10.1016/j.celrep.2015.08.069
M3 - Article
C2 - 26411689
AN - SCOPUS:84943261454
VL - 13
SP - 209
EP - 221
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 1
ER -
