Interrogating the Mechanism of Long Noncoding RNA ARInc-1 in Regulating AR Signaling
[Technical Report, Final Report]
University of Michigan
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Prostate cancer is the most commonly diagnosed non-skin cancer in American men, causing an estimated 31,620 cases of death in 2019. Androgens and Androgen Receptor AR pathways play critical roles in development and functions of the prostate gland. They are also necessary for prostate cancer progression. As such, primary androgen deprivation therapies and second generation anti-androgen drugs offer clinical benefits for patients with metastatic disease. However, nearly all patients with metastatic castration-resistant prostate cancermCRPC eventually develop resistance to these agents. Studies are thus warranted to discover novel players involved in the AR signaling pathway and in prostate cancer progression. To this end, we previously conducted transcriptome sequencing analysis to find long noncoding RNAs IncRNAs that are responsive to androgen stimulation, and are enriched in the process of prostate cancer progression. From this analysis, we identified IncRNA ARInc1, which is directly regulated by AR, and has lineage-specific, cancer associated expression pattern in prostate tissues. Phenotypic effects after knocking down this IncRNA include delayed cell proliferation, increased apoptosis, and attenuated AR signaling. We observed a positive feedback loop between ARInc1 and AR signaling. In this project, we interrogated the mechanisms through which ARInc1 regulates AR signaling pathway. We discovered that ARInc1 contributes to post-transcriptional regulation of AR transcript via RNA-RNA interaction. Moreover, ARInc1 inhibition by antisense technologies delays prostate cancer growth in vitro and in vivo. Taken together, out findings support a role for ARInc1 in maintaining AR signaling and identify ARInc1 as a novel therapeutic target.
- Medicine and Medical Research