Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Cell Death Differ. 2021 Jan;28(1):139-155. doi: 10.1038/s41418-020-0588-y. Epub 2020 Jul 16.
Ovarian cancer is the most lethal malignant tumor of female reproductive system. It is well-known that induction of STING-mediated type I interferons can enhance the resultant antitumor activity. However, STING pathway is usually inactivated in cancer cells at multiple levels. Here, we identified deubiquitinase USP35 is upregulated in ovarian cancer tissues. High level of USP35 was correlated with diminished CD8 T cell infiltration and poor prognosis in ovarian cancer patients. Mechanistically, we found that silencing USP35 reinforces the activation of STING-TBK1-IRF3 pathway and promotes the expression of type I interferons. Our data further showed that USP35 can directly deubiquitinate and inactivate STING. Interestingly, activation of STING promotes its binding to USP35 in a STING phosphorylation-dependent manner. Functionally, we found that knockdown of USP35 sensitizes ovarian cancer cells to the DNA-damage chemotherapeutic drug cisplatin. Overall, our study indicates that upregulation of USP35 may be a mechanism of the restricted STING activity in cancer cells, and highlights the significance of USP35 as a potential therapeutic target for ovarian cancer.
卵巢癌是女性生殖系统最致命的恶性肿瘤。众所周知，诱导 STING 介导的 I 型干扰素可以增强抗肿瘤活性。然而，STING 通路在癌症细胞中通常在多个水平失活。在这里，我们鉴定出去泛素化酶 USP35 在卵巢癌组织中上调。高水平的 USP35与卵巢癌患者 CD8 T 细胞浸润减少和预后不良相关。在机制上，我们发现沉默 USP35 增强了 STING-TBK1-IRF3 通路的激活，并促进了 I 型干扰素的表达。我们的数据进一步表明，USP35 可以直接去泛素化并失活 STING。有趣的是，STING 的激活以 STING 磷酸化依赖性的方式促进其与 USP35 的结合。在功能上，我们发现敲低 USP35 可使卵巢癌细胞对 DNA 损伤化疗药物顺铂敏感。总的来说，我们的研究表明，USP35 的上调可能是癌细胞中 STING 活性受限的一种机制，并强调了 USP35 作为卵巢癌潜在治疗靶点的重要性。
