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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Loss of Long Noncoding RNA NXTAR in Prostate Cancer Augments Androgen Receptor Expression and Enzalutamide Resistance
Ruchi Ghildiyal1,2, Mithila Sawant1,2, Arun Renganathan1,2
1Department of Surgery, Washington University in St. Louis, St. Louis, Missouri.
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), 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, pharmacologic 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. SIGNIFICANCE: This study identifies NXTAR 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.
Insights
A novel long noncoding RNA, NXTAR, suppresses prostate cancer by epigenetically downregulating androgen receptor (AR) and AR-V7 expression. Restoring NXTAR offers a potential therapy for enzalutamide-resistant prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Androgen receptor (AR) signaling drives prostate cancer, including castration-resistant prostate cancer (CRPC) resistant to enzalutamide.
- Resistance mechanisms in CRPC often involve continued AR signaling.
- Identifying novel regulators of AR is crucial for developing new therapies.
Purpose of the Study:
- To identify and characterize novel long noncoding RNAs (lncRNAs) involved in prostate cancer progression.
- To investigate the role of a newly identified lncRNA, NXTAR, in regulating AR expression and prostate cancer growth.
- To explore therapeutic strategies based on modulating NXTAR for treating enzalutamide-resistant prostate cancer.
Main Methods:
- Identification of NXTAR (LOC105373241) as a lncRNA repressed in prostate tumors.
- Investigated NXTAR's interaction with the AR promoter and its role in recruiting EZH2.
- Utilized small molecule inhibitor (R)-9b to block AR binding to the NXTAR promoter.
- Assessed the effect of NXTAR exon 5 oligonucleotide (NXTAR-N5) on AR expression and cell proliferation.
- Evaluated the efficacy of pharmacologic NXTAR restoration using (R)-9b in enzalutamide-resistant prostate cancer xenografts.
Main Results:
- NXTAR is located convergently with the AR gene and is downregulated in prostate tumors.
- NXTAR binds upstream of the AR promoter, recruits EZH2, and reduces AR and AR-V7 expression.
- AR binds the NXTAR promoter; inhibition of AR by (R)-9b releases this binding.
- GCN5 enhances NXTAR expression via H3K14 acetylation.
- NXTAR-N5 and (R)-9b treatment suppressed AR/AR-V7 expression, prostate cancer cell proliferation, and enzalutamide-resistant xenograft growth.
Conclusions:
- NXTAR acts as a tumor-suppressive lncRNA by epigenetically downregulating AR/AR-V7 expression.
- A positive feedback loop exists where NXTAR inhibits AR, which in turn upregulates NXTAR.
- Restoration of NXTAR represents a potential therapeutic strategy for recurrent CRPC resistant to enzalutamide.
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