Identification and Characterization of PLUTO-201, a Novel Long Non-Coding RNA Associated with Poor Outcomes in Prostate Cancer

Despite extensive investigation, the factors promoting aggressive prostate cancer are poorly understood. By performing a comprehensive analysis of whole-genome transcriptome data to identify differential expression across 1,567 patients with prostate cancer, we now report the identification of a novel lncRNA, Prostate Locus of Uncharacterized Transcript Outlier 201 (PLUTO-201), which is strongly associated with metastasis and poor overall survival in men with prostate cancer. We find that overexpression/knockdown of PLUTO-201 in pre-clinical models of prostate cancer modulates proliferation rates and markers of an aggressive phenotype through regulation of steroid biosynthesis and expression of the MHC class I complex, driving increased growth in androgen-depleted conditions and decreased susceptibility to T cell-mediated cytotoxicity. We further find that the heterogeneous nuclear ribonucleoprotein hnRNPK directly binds PLUTO-201 and is indispensable for its activity. Overall, our findings indicate that PLUTO-201 is a driver of aggressive prostate cancer phenotypes and poor clinical outcomes. Statement of SignificanceIdentification and characterization of PLUTO-201, a novel lncRNA driving aggressive biology in prostate cancer, sheds new light on the mechanisms driving aggressive prostate cancer and will motivate therapeutic and biomarker development. Statement of Translational RelevanceThe factors promoting prostate cancer progression and metastasis are poorly understood, resulting in a lack of therapeutic targets and prognostic biomarkers for this disease. Here, we have identified the novel long non-coding RNA (lncRNA) PLUTO-201 as strongly associated with prostate cancer progression and metastasis in patients with localized prostate cancer undergoing prostatectomy. We show that PLUTO-201 promotes proliferation, invasion, and metastasis in multiple prostate cancer models both in vitro and in vivo. Mechanistically, we find that PLUTO-201 downregulates MHC class 1 and upregulates steroid biosynthesis by interacting with the heterogeneous nuclear ribonucleoprotein K (hnRNPK), leading to decreased T cell-mediated cytotoxicity and increased resistance to androgen receptor inhibition. Altogether, this study provides strong evidence for a critical role of PLUTO-201 in prostate cancer progression and metastasis, and a rationale for further exploration of PLUTO-201 as a therapeutic target and prognostic biomarker for patients with prostate cancer.