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 significance: Identification 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 relevance: The 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.