Triple-negative breast cancer (TNBC) is a prevalent malignancy in women, casting a formidable shadow on their well-being. Positioned within the nucleolus, SUMO-specific protease 3 (SENP3) assumes a pivotal role in the realms of development and tumorigenesis. However, the participation of SENP3 in TNBC remains a mystery. Here, we elucidate that SENP3 exerts inhibitory effects on migration and invasion capacities, as well as on the stem cell–like phenotype, within TNBC cells. Further experiments showed that YAP1 is the downstream target of SENP3, and SENP3 regulates tumorigenesis in a YAP1-dependent manner. YAP1 is found to be SUMOylated and SENP3 deconjugates SUMOylated YAP1 and promotes degradation mediated by the ubiquitin-proteasome system. More importantly, YAP1 with a mutation at the SUMOylation site impedes the capacity of WT YAP1 in TNBC tumorigenesis. Taken together, our findings firmly establish the pivotal role of SENP3 in the modulation of YAP1 deSUMOylation, unveiling novel mechanistic insight into the important role of SENP3 in the regulation of TNBC tumorigenesis in a YAP1-dependent manner.

中文翻译：

---

SENP3 介导 YAP1 的去 SUMO 化和降解，以调节三阴性乳腺癌的进展


三阴性乳腺癌 （TNBC） 是女性普遍存在的恶性肿瘤，给她们的健康蒙上了可怕的阴影。位于核仁内的 SUMO 特异性蛋白酶 3 （SENP3） 在发育和肿瘤发生领域起着关键作用。然而，SENP3 参与 TNBC 仍然是一个谜。在这里，我们阐明了 SENP3 对 TNBC 细胞内的迁移和侵袭能力以及干细胞样表型产生抑制作用。进一步的实验表明，YAP1 是 SENP3 的下游靶点，SENP3 以 YAP1 依赖性方式调节肿瘤发生。发现 YAP1 被 SUMO 化，SENP3 去偶联 SUMO 化的 YAP1 并促进泛素-蛋白酶体系统介导的降解。更重要的是，在 SUMO化位点发生突变的 YAP1 阻碍了 WT YAP1 在 TNBC 肿瘤发生中的能力。综上所述，我们的研究结果坚定地确立了 SENP3 在调节 YAP1 deSUMOylation 中的关键作用，揭示了 SENP3 在 YAP1 依赖性方式调节 TNBC 肿瘤发生中的重要作用的新机制见解。