Investigation of HIF-dependent and -independent tumor suppressor functions of VHL

描述（由申请人提供）：肾癌是一种致命的疾病，尽管出现了新的治疗方法。VHL肿瘤抑制基因的失活在肾透明细胞癌（ccRCC）的发病机制中起着因果作用，肾透明细胞癌是一种病理亚型，占肾癌的大多数。然而，pVHL的肿瘤抑制机制仍不完全清楚。pVHL功能的丧失导致HIF的组成性激活，这对于肿瘤的形成至关重要。在临床上，部分阻断活化的HIF通路的抗血管生成药物对ccRCC显示出阳性但短暂的临床活性。虽然HIF激活对于肾癌的形成和维持至关重要，但它本身并不足以导致ccRCC。最近发现pVHL负调节EGFR的活性，EGFR是一种受体酪氨酸激酶，当在许多癌症中异常激活时是致癌的。该提案将研究pVHL如何通过多种机制拮抗EGFR：a）促进c-Cbl非依赖性多聚泛素化和活化EGFR的降解; B）通过抑制JARID 1C以维持总体H3 K4 Me 3水平来转录影响EGFR信号传导。（H3 K4 Me 3对活跃的基因转录至关重要）;和c）通过EGFR磷酸酶维持VHL+/+ ccRCC细胞中EGFR对其抑制剂的敏感性。这些研究将揭示和阐明pVHL新的肿瘤抑制功能。它还将揭示最近在ccRCC中发现的癌症基因JARID 1C的肿瘤抑制功能，并揭示其对EGFR信号传导的影响。最后，这项研究还将提供关于为什么VHL缺陷型ccRCC肿瘤对EGFR抑制剂（EGFRi）耐药的见解。这些知识可以导致将EGFRi转化为针对这些肿瘤的有效治疗方法。 公共卫生相关性：肾癌是一种致命的疾病，需要有效的管理。VHL肿瘤抑制基因的失活在大多数肾癌的发病机制中起着因果作用，但其肿瘤抑制机制仍不完全清楚。pVHL的HIF依赖性和HIF非依赖性肿瘤抑制功能的拟议研究将提供pVHL如何工作的详细机制的理解和知识可能提供新的方法治疗干预肾癌。

DESCRIPTION (provided by applicant): Kidney cancer is a deadly disease despite the emergence of new treatments. Inactivation of the VHL tumor suppressor gene plays a causal role in the pathogenesis of clear cell renal carcinomas (ccRCC), a pathological subtype that accounts for the majority of kidney cancer. However, the tumor suppressing mechanism(s) of pVHL remains incompletely understood. Loss of functions of pVHL leads to constitutive activation of HIF, which was critical for tumor formation. In clinic, anti-angiogenesis drugs that partially block the activated HIF pathway have shown positive but transient clinical activity against ccRCC. Although HIF activation is critical for formation and maintenance of kidney cancer, it alone is not enough to cause ccRCC. It was recently discovered that pVHL negatively regulates the activity of EGFR, a receptor tyrosine kinase that is oncogenic when abnormally activated in many cancers. This proposal will investigate how pVHL antagonizes EGFR through multiple mechanisms: a) promoting c-Cbl-independent poly-ubiquitylation and degradation of activated EGFR; b) affecting EGFR signaling transcriptionally by suppressing JARID1C to maintain the overall H3K4Me3 level (H3K4Me3 is critical for active gene transcription); and c) maintaining the sensitivity of EGFR to its inhibitors in VHL+/+ ccRCC cells through an EGFR phosphatase. The proposed studies will uncover and elucidate new tumor-suppressing functions of pVHL. It will also shed light on the tumor-suppressive function of JARID1C, a cancer gene recently identified in ccRCC, and reveal its effect on EGFR signaling. Finally, this study will also provide insights as to why VHL-defective ccRCC tumors are resistant to EGFR inhibitors (EGFRi). Such knowledge can lead to ways to transform EGFRi into effective therapeutics against these tumors.) PUBLIC HEALTH RELEVANCE: Kidney cancer is a deadly disease that requires effective management. Inactivation of the VHL tumor suppressor gene plays a causal role in the pathogenesis of the majority of kidney cancer but its tumor suppressing mechanism(s) remains incompletely understood. The proposed study of HIF-dependent and HIF-independent tumor suppressor functions of pVHL will provide detailed mechanistic understanding of how pVHL works and the knowledge might provide new ways of therapeutic intervention for kidney cancer.