HULLK, a novel lncRNA that functions as a targetable oncogene in PCa

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Abstract There remains a critical need for more effective therapies for prostate cancer and for castration resistant prostate cancer. While localized prostate cancer (PCa) has a favorable prognosis, castration-resistant prostate cancer (CRPC) remains incurable. The failure of current therapies demonstrates a need for new approaches, and exposes an incomplete understanding of the underlying mechanisms that drive PCa to CRPC. Long noncoding RNAs (lncRNAs) have been underappreciated as critical regulatory elements of many cellular biological processes relevant to cancer development and progression. These IncRNAs may be targets for potent new therapies to combat PCa progression. We have recently published the discovery of a novel lncRNA that acts as an oncogene in PCa. This unannotated lncRNA is dramatically upregulated by androgen in a dose-dependent manner and the hormone-induced increase is completely blocked by the anti-androgen enzalutamide. We have named this lncRNA “HULLK” for Hormone-Upregulated lncRNA within LCK. HULLK transcripts are expressed in patient tissue and there is a significant positive correlation between HULLK expression and high-grade PCa in three independent cohorts: The Cancer Genome Atlas, the University of Virginia, and the University of Texas Southwestern. Important for potential therapeutics, shRNAs specifically targeting HULLK significantly decreased PCa cell growth, including CRPC cells expressing the ligand independent ARv7. These data lead to the hypothesis that HULLK is a novel lncRNA that functions as a targetable oncogene in PCa. In this proposal we will test HULLK as a driver of PCa in patient-derived xenograft in vivo models, provide proof-of-concept therapeutic targeting of HULLK, and identify HULLK binding partners, which is the critical first step for determining the molecular mechanism of HULLK. This proposal integrates innovative conceptual, technical, and translational elements to uncover the molecular mechanisms through which HULLK drives PCa and to evaluate HULLK as a potential therapeutic target in this devastating disease.