去泛素化酶(DUB)已成为癌症治疗的有希望的靶标,因为它们在泛素机制中稳定底物蛋白中的作用。这里,我们通过筛查乳腺癌中的预后DUB,将泛素特异性蛋白酶26(USP26)鉴定为癌基因.通过体外和体内实验,我们发现USP26的耗竭抑制了乳腺癌细胞的增殖和侵袭,并抑制裸鼠的肿瘤生长和转移。进一步的研究确定了与Bcl-2相关的基因3(BAG3)作为USP26的直接底物,并且BAG3的异位表达部分逆转了USP26敲低诱导的抗肿瘤作用。机械上,赖氨酸乙酰转移酶Tip60在K134靶向USP26进行乙酰化,这增强了USP26与BAG3的结合亲和力,导致BAG3去泛素化和增加的蛋白质稳定性。重要的是,我们采用了基于结构的虚拟筛选,发现了一种名为5813669的药物样分子,该分子靶向USP26,使BAG3不稳定,并在体内有效减缓肿瘤生长和转移.临床上,USP26的高表达水平与乳腺癌患者BAG3水平升高和预后不良相关.总的来说,我们的研究结果强调了USP26在BAG3蛋白稳定中的关键作用,并为乳腺癌提供了一个有前景的治疗靶点.
Deubiquitylases (DUBs) have emerged as promising targets for cancer therapy due to their role in stabilizing substrate proteins within the ubiquitin machinery. Here, we identified ubiquitin-specific protease 26 (USP26) as an oncogene via screening prognostic DUBs in breast cancer. Through in vitro and in vivo experiments, we found that depletion of USP26 inhibited breast cancer cell proliferation and invasion, and suppressed tumor growth and metastasis in nude mice. Further investigation identified co-chaperone Bcl-2-associated athanogene 3 (BAG3) as the direct substrate of USP26, and ectopic expression of BAG3 partially reversed antitumor effect induced by USP26 knockdown. Mechanistically, the lysine acetyltransferase Tip60 targeted USP26 at K134 for acetylation, which enhanced USP26 binding affinity to BAG3, leading to BAG3 deubiquitination and increased protein stability. Importantly, we employed a structure-based virtual screening and discovered a drug-like molecule called 5813669 that targets USP26, destabilizing BAG3 and effectively mitigating tumor growth and metastasis in vivo. Clinically, high expression levels of USP26 were correlated with elevated BAG3 levels and poor prognosis in breast cancer patients. Overall, our findings highlight the critical role of USP26 in BAG3 protein stabilization and provide a promising therapeutic target for breast cancer.