Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
Translational Cancer Research Center, Peking University First Hospital, 100034, Beijing, China.
Oncogene. 2022 Apr;41(16):2265-2274. doi: 10.1038/s41388-022-02252-7. Epub 2022 Mar 2.
Dual-specificity mitogen-activated protein kinase phosphatase-1 (MKP-1/DUSP1/CL-100) has been documented to promote breast cancer cell survival and chemoresistance. MKP-1 is an unstable protein that is ubiquitinated and degraded via the ubiquitin-proteasome system. However, it is not clear how MKP-1 protein stability is regulated in breast cancer. In this study, we performed a genome-wide siRNA library screen of deubiquitinases (DUBs) and identified STAMBPL1 as an MKP-1 DUB in breast cancer cells. STAMBPL1 interacts with MKP-1 and stabilizes MKP-1 via deubiquitination. Both STAMBPL1 and MKP-1 depletion sensitize breast cancer cells to cisplatin in vitro and in vivo, and ectopic overexpression of MKP-1 partially rescues STAMBPL1 depletion-induced cisplatin sensitivity. Furthermore, STAMBPL1 and MKP-1 depletion increased breast cancer sensitivity to cisplatin by increasing the phosphorylation and activation of c-Jun N-terminal protein kinase (JNK). Collectively, our findings not only identify STAMBPL1 as an MKP-1 DUB but also reveal a critical mechanism that regulates MKP-1 expression in breast cancer. Our findings indicate that the STAMBPL1/MKP-1 axis represents a potential therapeutic target in breast cancer.
双特异性丝裂原活化蛋白激酶磷酸酶-1（MKP-1/DUSP1/CL-100）已被证明可促进乳腺癌细胞的存活和化疗耐药性。MKP-1 是一种不稳定的蛋白质，可通过泛素-蛋白酶体系统进行泛素化和降解。然而，MKP-1 蛋白稳定性如何在乳腺癌中受到调节尚不清楚。在这项研究中，我们对去泛素酶（DUBs）进行了全基因组 siRNA 文库筛选，鉴定出 STAMBPL1 是乳腺癌细胞中的一种 MKP-1 DUB。STAMBPL1 与 MKP-1 相互作用，并通过去泛素化稳定 MKP-1。STAMBPL1 和 MKP-1 的缺失均使乳腺癌细胞对顺铂的体外和体内敏感性增加，而过表达 MKP-1 可部分挽救 STAMBPL1 缺失诱导的顺铂敏感性。此外，STAMBPL1 和 MKP-1 的缺失通过增加 c-Jun N 端蛋白激酶（JNK）的磷酸化和激活来增加乳腺癌对顺铂的敏感性。总之，我们的研究结果不仅鉴定出 STAMBPL1 是一种 MKP-1 DUB，还揭示了调节乳腺癌中 MKP-1 表达的关键机制。我们的研究结果表明，STAMBPL1/MKP-1 轴代表了乳腺癌的一个潜在治疗靶点。
