title: LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer.
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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Zhao
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Fong
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Yeqing Angela
authors.initials: YA
authors.lastname: Yang
authors.affiliation: Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Chakravarti
authors.affiliation: Department of Pharmacology/Toxicology and Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Yin-Yuan
authors.initials: YY
authors.lastname: Mo
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: jindan-yu@northwestern.edu.
authors.forename: Jindan
authors.initials: J
authors.lastname: Yu
mesh_terms: D000728:Androgens / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D000728:Androgens; C561566:HOTAIR long untranslated RNA, human; D062085:RNA, Long Noncoding; D011944:Receptors, Androgen; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex