NF2抑癌基因突变相关肿瘤的分子致病机理和治疗方法

The tumor suppressor NF2 is inactivated in the cancer predisposition syndrome Neurofibromatosis type 2, in a large fraction of malignant pleural mesotheliomas, and in a smaller percentage of other tumor types. In spite of intensive efforts dating back almost 20 years, the function of Merlin in normal physiology and tumor suppression remains incompletely understood. Our previous studies indicated that Merlin suppresses tumorigenesis by entering into the nucleus, where it binds to and inhibits the E3 ubiquitin ligase CRL4-DCAF1. Our recent studies found that this ligase can activate the Hippo pathway oncoprotein YAP. Such regulation appears to be through the YAP kinase Lats. Based on these results, we hypothesize that Lats is the substrate of CRL4-DCAF1. By promoting Lats ubiquitylation, CRL4-DCAF1 inhibits Lats activity, thereby activating YAP. We will employ approaches in biochemistry, cell biology and genetics to examine if CRL4-DCAF1 induces Lats ubiquitylation, inhibits its activity and activates YAP-mediated oncogenesis. We will also use tumorigenesis models and pharmacological approaches to examine if a small chemical inhibitor, MLN4924, can inhibit CRL4-DCAF1 and show the therapeutic efficacy. The above studies will benefit to understand Merlin tumor suppressor function and pave the way for using MLN4929 in a novel therapy of NF2-related tumors.

NF2抑癌基因的突变会引起一系列肿瘤疾病。该基因编码Merlin蛋白质。虽然该蛋白已经被发现了二十多年，它抑制肿瘤发生的分子机理还不清楚。我们的前期工作发现Merlin的抑癌功能是通过进入细胞核并抑制一个泛素连接酶CRL4-DCAF1来完成的。我们还发现该泛素连接酶能够激活YAP致癌蛋白。这一调节依赖于YAP的磷酸化激酶Lats。在此基础上，我们假设Lats是该泛素连接酶的底物。通过泛素化调节，该泛素连接酶抑制Lats的激酶活性，从而激活YAP。我们将通过生物化学，细胞生物学和遗传学等技术来探索该泛素连接酶能否促进Lats的泛素化，并通过抑制Lats来激活YAP介导的肿瘤发生。我们也将利用肿瘤模型和药物学的方法来检查是否用MLN4924药物来抑制该泛素连接酶能够具有治疗效果。本研究对阐明NF2突变相关肿瘤的致病机理具有重要意义；并为把MLN4924用于治疗这些肿瘤疾病奠定基础。