PDF(Pubmed)
Abstract：
The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.
摘要：
VonHippel-Lindau(VHL)蛋白，在透明细胞肾细胞癌（ccRCC）中经常发生突变，是参与氧化应激的缺氧诱导因子（HIF）的主要调节因子。然而,VHL是否具有不依赖HIF的肿瘤抑制活性尚不清楚.这里,我们证明VHL抑制营养应激诱导的自噬，散发性ccRCC标本中其缺乏与自噬水平显著升高有关，并与患者预后较差相关。机械上,VHL在其PHD1介导的Pro54上的羟基化后直接与自噬调节因子Beclin1结合。这种结合抑制了Beclin1-VPS34复合物与ATG14L的缔合，从而抑制对营养缺乏反应的自噬启动。非羟基化Beclin1P54A的表达消除了VHL介导的自噬抑制，并显着降低了VHL的肿瘤抑制作用。此外,在野生型表达VHL的人ccRCC标本中，Beclin1P54-OH水平与自噬水平呈负相关，患者预后差。此外，用自噬抑制剂和HIF2α抑制剂联合治疗VHL缺陷小鼠肿瘤可抑制肿瘤生长。这些发现揭示了VHL抑制肿瘤生长的一个意想不到的机制，并建议通过联合抑制自噬和HIF2α来治疗ccRCC。
