Zhang Shengzhe, Zhang Meiying, Jing Ying, Yin Xia, Ma Pengfei, Zhang Zhenfeng, Wang Xiaojie, Di Wen, Zhuang Guanglei
State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200240, China.
Nat Commun. 2018 Jan 15;9(1):215. doi: 10.1038/s41467-017-02693-9.
MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.
MCL1是抗凋亡BCL-2家族蛋白的关键成员。虽然MCL1的一个显著特征在于其高效的泛素化和降解，但去泛素化酶USP9X已被证明可通过去除多聚泛素链来维持MCL1的表达。在此，我们进行了一项无偏向性的siRNA筛选，并确定第二种去泛素化酶USP13在肺癌和卵巢癌细胞中调节MCL1的稳定性。从机制上讲，USP13通过去泛素化与MCL1相互作用并使其稳定。因此，使用CRISPR/Cas9核酸酶系统敲除USP13可抑制异种移植裸鼠中的肿瘤生长。我们进一步报道，对USP13进行基因或药物抑制可显著降低MCL1蛋白丰度，并显著增加肿瘤细胞对靶向BCL-2和BCL-XL的BH3模拟物抑制剂的敏感性。总体而言，我们将USP13确定为一种新型去泛素化酶，它在多种实体瘤中调节MCL1的周转，并提出USP13可能是治疗各种恶性肿瘤的潜在治疗靶点。
