CDK4/6-BAP1-VHL信号轴促进肿瘤肝转移机制研究及CDK4/6抑制剂新适应症的发现

远端器官转移是实体瘤患者的主要致死原因和治疗难题。肿瘤干细胞（CSCs）在特定靶器官定植生长(colonization)是肿瘤转移的限速步骤，但机制不清楚。缺氧诱导因子HIF1α能促进CSCs，HIF1α受其E3连接酶VHL调控。我们的前期研究表明：去泛素化酶BAP1能增加VHL蛋白的稳定性、抑制葡萄膜黑色素瘤的肝转移，CDK4/6能磷酸化BAP1并削弱BAP1对VHL的稳定作用。我们据此提出假说：CDK4/6磷酸化BAP1而抑制后者的去泛素化酶活性，降低VHL从而升高HIF1α，促进CSCs干性及其定植生长，而靶向CDK4/6的药物Palbociclib等能阻断这一级联反应从而抑制肝转移。本课题旨在通过检验这一科学假说，明确CDK4/6-BAP1-VHL信号轴的精细调节机制，并把这一信号轴外延到结直肠癌的肝转移进行验证，为肝转移的防治提供新靶点，也为Palbociclib等找到新适应。

Metastasis resulting from disseminated cancer cells that initiate new tumors at distant organ sites, is one of the primary causes of cancer-related deaths. The colonization of cancer stem-like cells (CSCs) in distant organ sites is a rate-limiting phase of metastasis and remains poorly understood. Hypoxia-inducible factor 1α (HIF1α) promotes CSCs which is regulated by its E3 ligase VHL. Our preliminary data demonstrated that BAP1 deubiquitinated and thereby stabilized VHL, and profoundly inhibited hepatic metastasis in uveal melanoma. The phosphorylation of BAP1 by CDK4/6 destabilized VHL protein. These findings prompted us to hypothesize that BAP1 phosphorylation by CDK4/6 may lead to inhibition BAP1 deubiquitination enzyme activity, and destabilize VHL, which subsequently increases HIF1α to promote the stemness of CSCs and colonization. This cascade can be blocked by Palbociclib inactivating CDK4/6 serine/threonine kinases, which can ameliorate liver metastasis. This proposal is aimed at testing this hypothesis to precisely elucidate the mechanistic regulation of the CDK4/6-BAP1-VHL signaling axis, and its role in liver metastasis in uveal melanoma and colorectal carcinoma. This study will validate potential therapeutic targets for liver metastasis and find the new indications for FDA approved CDK4/6 inhibitors such as Palbociclib.