Loss of Long Noncoding RNA <i>NXTAR</i> in Prostate Cancer Augments Androgen Receptor Expression and Enzalutamide Resistance.

Abstract

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), <i>NXTAR</i> (LOC105373241) that is located convergent with the AR gene and is repressed in human prostate tumors and cell lines. <i>NXTAR</i> bound upstream of the <i>AR</i> promoter and promoted EZH2 recruitment, causing significant loss of AR (and AR-V7) expression. Paradoxically, AR bound the <i>NXTAR</i> promoter, and inhibition of AR by the ACK1/TNK2 small molecule inhibitor (<i>R</i>)-<b>9b</b> excluded AR from the <i>NXTAR</i> promoter. The histone acetyltransferase GCN5 bound and deposited H3K14 acetylation marks, enhancing <i>NXTAR</i> expression. Application of an oligonucleotide derived from <i>NXTAR</i> 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 <i>NXTAR</i> using (<i>R</i>)-<b>9b</b> abrogated enzalutamide-resistant prostate xenograft tumor growth. Overall, this study uncovers a positive feedback loop, wherein <i>NXTAR</i> acts as a novel prostate tumor-suppressing lncRNA by inhibiting AR/AR-V7 expression, which in turn upregulates <i>NXTAR</i> 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 <i>NXTAR</i> 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.