Androgen receptor (AR) signaling continues to play a dominant role in all stages of prostate cancer (PC), including castration-resistant prostate cancers (CRPC) that have developed resistance to second-generation AR antagonists such as enzalutamide. In this study, we identified a long non-coding RNA (lncRNA), NXTAR (LOC105373241), that is located convergent with the AR gene and is repressed in human prostate tumors and cell lines. NXTAR bound upstream of the AR promoter and promoted EZH2 recruitment, causing significant loss of AR (and AR-V7) expression. Paradoxically, AR bound the NXTAR promoter, and inhibition of AR by the ACK1/TNK2 small molecule inhibitor (R)-9b excluded AR from the NXTAR promoter. The histone acetyltransferase GCN5 bound and deposited H3K14 acetylation marks, enhancing NXTAR expression. Application of an oligonucleotide derived from NXTAR exon 5 (NXTAR-N5) suppressed AR/AR-V7 expression and prostate cancer cell proliferation, indicating the translational relevance of the negative regulation of AR. In addition, pharmacological restoration of NXTAR using (R)-9b abrogated enzalutamide-resistant prostate xenograft tumor growth. Overall, this study uncovers a positive feedback loop, wherein NXTAR acts as a novel prostate tumor-suppressing lncRNA by inhibiting AR/AR-V7 expression, which in turn upregulates NXTAR levels, compromising enzalutamide-resistant prostate cancer. The restoration of NXTAR could serve as a new therapeutic modality for patients who have acquired resistance to second-generation AR antagonists.
Cancer research. 2021 Nov 05 [Epub ahead of print]
Ruchi Ghildiyal, Mithila Sawant, Arun Renganathan, Kiran Mahajan, Eric H Kim, Jingqin Luo, Ha X Dang, Christopher A Maher, Felix Y Feng, Nupam P Mahajan
Siteman Cancer Center, Moffitt Cancer Center., Surgery, Washington University in St. Louis., Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis School of Medicine., Internal Medicine, Washington University in St. Louis., Oncology Division, Washington University in St. Louis School of Medicine., Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco., Siteman Cancer Center, Moffitt Cancer Center .