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肿瘤抑制基因失活在透明细胞肾癌（ccRCC）的发病机制中起着因果作用，透明细胞肾癌是肾癌的主要病理亚型。然而，pVHL的抑瘤机制尚不完全清楚。pVHL功能的丧失导致HIF的组成性激活，这对肿瘤的形成至关重要。在临床上，部分阻断激活的HIF通路的抗血管生成药物对ccRCC表现出阳性但短暂的临床活性。尽管HIF激活对肾癌的形成和维持至关重要，但仅靠HIF激活不足以引起ccRCC。最近发现pVHL负调控EGFR的活性，EGFR是一种受体酪氨酸激酶，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)促进不依赖c- cl的多泛素化和活化EGFR的降解；b)通过抑制JARID1C来影响EGFR信号的转录，以维持整体H3K4Me3水平（H3K4Me3对活性基因转录至关重要）；c)通过EGFR磷酸酶维持VHL+/+ ccRCC细胞中EGFR对其抑制剂的敏感性。所提出的研究将揭示和阐明pVHL的新的肿瘤抑制功能。它还将揭示JARID1C（最近在ccRCC中发现的一种癌症基因）的肿瘤抑制功能，并揭示其对EGFR信号传导的影响。最后，本研究还将提供关于为什么vhl缺陷的ccRCC肿瘤对EGFR抑制剂（EGFRi）具有耐药性的见解。这些知识可以引导将EGFRi转化为有效治疗这些肿瘤的方法。)

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.)