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

摘要 对于前列腺癌和去势抵抗性前列腺癌，仍然迫切需要更有效的疗法。 癌虽然局限性前列腺癌（PCa）具有良好的预后，但去势抵抗性前列腺癌（PCa） CRPC仍然无法治愈。目前治疗的失败表明需要新的方法， 暴露了对驱动PCa至CRPC的潜在机制的不完整理解。长非编码 RNA（lncRNA）作为许多细胞生物学过程的关键调控元件一直被低估。 与癌症发展和进展相关的过程。这些IncRNA可能是有效的新靶点。 治疗以对抗PCa进展。我们最近发表了一种新的lncRNA的发现， PCa中的癌基因。这种未注释的lncRNA被雄激素以剂量依赖性方式显著上调。 抗雄激素Enzalutamide可完全阻断雄激素诱导的增加。我们有 将这种lncRNA命名为“HULLK”，表示LCK内的激素上调的lncRNA。HULLK转录本在 患者组织中HULLK表达与高级别PCa之间存在显著正相关， 三个独立的队列：癌症基因组图谱，弗吉尼亚大学和德克萨斯大学 西南部对于潜在的治疗重要的是，特异性靶向HULLK的shRNA显著减少了 PCa细胞生长，包括表达配体非依赖性ARv7的CRPC细胞。这些数据导致 假设HULLK是一种新的lncRNA，在PCa中作为靶向癌基因发挥作用。在本提案中，我们 将在患者来源的异种移植物体内模型中测试HULLK作为PCa的驱动因素，提供概念验证 HULLK的治疗靶向，并确定HULLK结合伴侣，这是关键的第一步， 确定HULLK的分子机制。该提案将创新的概念、技术和 翻译元件，以揭示HULLK驱动PCa的分子机制，并评估 HULLK作为这种毁灭性疾病的潜在治疗靶点。

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.