Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, 310029, Hangzhou, China.
Cancer Center, Zhejiang University, 310029, Hangzhou, Zhejiang, China.
EMBO J. 2024 Mar;43(6):931-955. doi: 10.1038/s44318-024-00051-2. Epub 2024 Feb 15.
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.
希佩尔-林道（VHL）蛋白在肾透明细胞癌（ccRCC）中经常发生突变，是缺氧诱导因子（HIF）的主要调节因子，参与氧化应激。然而，VHL 是否具有 HIF 非依赖性的肿瘤抑制活性在很大程度上仍不清楚。在这里，我们证明 VHL 抑制营养应激诱导的自噬，并且散发性 ccRCC 标本中 VHL 的缺乏与自噬水平的显著升高有关，并与患者预后较差相关。在机制上，VHL 在 PHD1 介导的 Pro54 羟化作用后直接与自噬调节剂 Beclin1 结合。这种结合抑制了 Beclin1-VPS34 复合物与 ATG14L 的结合，从而抑制了对营养缺乏的自噬起始。表达不可羟化的 Beclin1 P54A 可消除 VHL 介导的自噬抑制作用，并显著降低 VHL 的肿瘤抑制作用。此外，Beclin1 P54-OH 水平与野生型 VHL 表达的人 ccRCC 标本中的自噬水平呈负相关，与患者预后不良相关。此外，用自噬抑制剂和 HIF2α 抑制剂联合治疗 VHL 缺陷型小鼠肿瘤可抑制肿瘤生长。这些发现揭示了 VHL 抑制肿瘤生长的一种意外机制，并提示通过联合抑制自噬和 HIF2α 可能为 ccRCC 提供一种潜在的治疗方法。
