USP22 is a Novel Target for Prostate Cancer Therapy

描述（由申请人提供）：前列腺癌（PCa）是美国最常见的恶性肿瘤，也是男性癌症死亡的第二大原因。虽然局部疾病可以有效治疗，但对于非器官局限性疾病尚无有效的治疗方法。前列腺癌在所有阶段都依赖于雄激素受体（AR）信号；因此，消融AR活性（称为雄激素剥夺疗法）是播散性肿瘤治疗干预的第一线。虽然最初有效，但由于不适当地恢复AR活性，复发性“去势抵抗性”前列腺癌（CRPC）在2-3年内发展。多种途径可诱导复发性AR活动，但最常观察到的改变是AR本身的积累增强。此外，一小部分协同致癌基因，特别是c-Myc，已被证明与AR协同作用，诱导疾病进展。由于目前还没有有效的治疗方法来治疗这种无法治愈的疾病，因此有必要确定导致AR活性和CRPC复苏的机制，并设计有效的CRPC管理新疗法。该应用程序确定了泛素特异性肽酶22 （USP22）去泛素化酶作为AR和c-Myc活性的组合效应物，在PCa中上调，其活性为治疗干预提供了一种新的靶向分子。几个关键的初步研究结果表明：1 . USP22在前列腺癌中显著上调；(二)。USP22调控c-Myc转录激活功能；3。USP22是AR积累和活性的有效调节剂；iv. USP22是驱动CRPC形成的截断受体积累所必需的；和v)USP22对于ar依赖性PCa和CRPC的高效增殖至关重要。基于这些数据，我们假设USP22在肿瘤形成和向耐药疾病的转变中发挥作用。这一假设将在两个方面得到检验。首先，USP22控制c-Myc和AR的机制将在早期和耐药性疾病的细胞模型中进行测试。该方法涉及USP22表达的缺失和c-Myc和AR活性的分析，这些活性与靶基因转录、蛋白质稳定性/半衰期、蛋白酶体的贡献和细胞周期谱有关。其次，将确定USP22与前列腺癌生长和进展的相关性。将采用原位异种移植模型来研究USP22缺失或过表达对激素敏感和治疗耐药PCa的影响。结果将根据肿瘤生长、肿瘤内增殖和血清PSA水平（AR活性的代表）来评估。本实验设计是分析USP22调节控制PCa疾病形成和进展的两种致癌信号活性的能力的一种合乎逻辑且有效的方法。总之，这一提议支持了USP22是PCa中AR稳定性和c-Myc活性的主要调节因子的假设，可以有效地针对人类疾病预防和治疗CRPC。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most commonly diagnosed malignancy and second leading cause of male cancer death in the U.S. While local disease can be effectively treated, there is no effective cure for non-organ confined disease. PCa is exquisitely dependent on androgen receptor (AR) signaling at all stages; therefore, ablation of AR activity (known as androgen deprivation therapy) is the first line of therapeutic intervention for disseminated tumors. While initially effective, recurrent, 'castrate-resistant' prostate cancers (CRPC) develop within 2-3 years as a result of inappropriately restored AR activity. Multiple pathways can induce recurrent AR activity but the most frequently observed alteration is enhanced accumulation of AR itself. Additionally, a small subset of cooperating oncogenes, especially c-Myc, has been shown to act in concert with AR to induce disease progression. Since no effective treatment has been identified for this incurable stage of disease, there is a significant need to determine the mechanisms that contribute to resurgent AR activity and CRPC, and to design effective new therapeutics for CRPC management. This application identifies the Ubiquitin-Specific Peptidase 22 (USP22) deubiquitylating enzyme as a combinatorial effector of both AR and c-Myc activity that is upregulated in PCa, and whose activity affords a novel, targetable molecule for therapeutic intervention. Several key preliminary findings demonstrate that: i. USP22 is significantly upregulated in prostate cancer; ii). USP22 regulates c-Myc transcriptional activation function; iii. USP22 is a potent regulator of AR accumulation and activity; iv. USP22 is required for accumulation of truncated receptors that drive CRPC formation; and v.) USP22 is critical for efficient AR-dependent PCa and CRPC proliferation. Based on these data, we hypothesize that USP22 is playing a role in tumor formation and transition to resistant disease. This hypothesis will be tested in two aims. First, the mechanism by which USP22 controls c-Myc and AR will be tested in cell models of both early stage and resistance disease. This approach involves depletion of USP22 expression and analysis of c-Myc and AR activity with respect to target gene transcription, protein stability/half- life, contribution of the proteasome, and cell cycle profile. Second, the relevance of USP22 towards PCa growth and progression will be determined. Orthotopic xenograft models will be employed to investigate the impact of USP22 depletion or overexpression in hormone sensitive and therapy resistant PCa. The outcome will be appraised based on tumor growth, intratumor proliferation, and serum PSA levels (representative of AR activity). This experimental design is a logical and efficient method to analyze the ability of USP22 to regulate the activity of two oncogenic signals that control PCa disease formation and progression. Together this proposal supports the hypothesis that USP22 is a master regulator of AR stability and c-Myc activity in PCa that could be effectively targeted in human disease for prevention and treatment of CRPC.