Loss of Long Noncoding RNA in Prostate Cancer Augments Androgen Receptor Expression and Enzalutamide Resistance.

Androgen receptor (AR) signaling continues to play a dominant role in all stages of prostate cancer, 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 noncoding RNA (lncRNA), (LOC105373241) that is located convergent with the AR gene and is repressed in human prostate tumors and cell lines. bound upstream of the promoter and promoted EZH2 recruitment, causing significant loss of AR (and AR-V7) expression. Paradoxically, AR bound the promoter, and inhibition of AR by the ACK1/TNK2 small molecule inhibitor ()- excluded AR from the promoter. The histone acetyltransferase GCN5 bound and deposited H3K14 acetylation marks, enhancing expression. Application of an oligonucleotide derived from 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, pharmacologic restoration of using ()- abrogated enzalutamide-resistant prostate xenograft tumor growth. Overall, this study uncovers a positive feedback loop, wherein acts as a novel prostate tumor-suppressing lncRNA by inhibiting AR/AR-V7 expression, which in turn upregulates 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. SIGNIFICANCE: This study identifies as a tumor suppressive lncRNA that can epigenetically downregulate AR/AR-V7 expression and provides a therapeutic strategy to reinstate NXTAR expression for treating recurrent CRPC.