Zhou Li, Zheng Chanjuan, Ding Siyu, Wang Zhiyu, Yang Yiyuan, Wang Yian, He Guangchun, Fu Shujun, Deng Xiyun
Key Laboratory of Translational Cancer Stem Cell Research, Department of Pathophysiology, Hunan Normal University, Changsha 410013, China.
Department of Pathology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
Cells. 2025 May 31;14(11):816. doi: 10.3390/cells14110816.
Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2) expression, represents a therapeutic challenge due to its aggressive nature and limited treatment options. Here, we identified the cholesterol-lowering drug lovastatin (LV) as a potent apoptosis-inducing agent in TNBC. Mechanistically, LV disrupts the interaction between the deubiquitinating enzyme USP14 and Survivin, a key anti-apoptotic protein, enhancing polyubiquitination and the proteasomal degradation of Survivin. The overexpression of USP14 was found to stabilize Survivin and rescue LV-induced apoptosis and tumor suppression in vitro and in vivo, whereas USP14 silencing or inhibition with IU1 (a USP14-specific inhibitor) enhanced Survivin turnover and synergized with LV to suppress colony formation in TNBC cells. Clinical relevance was demonstrated through bioinformatic analysis and immunohistochemistry, revealing that elevated Survivin expression in TNBC tissues correlated with poor prognosis and is significantly upregulated in TNBC versus non-TNBC tissues. Our findings identify the USP14-Survivin axis as a potential therapeutic target and highlight LV as a promising candidate for TNBC treatment.
三阴性乳腺癌（TNBC）的特征是缺乏雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）表达，由于其侵袭性本质和有限的治疗选择，它代表了一种治疗挑战。在此，我们确定降胆固醇药物洛伐他汀（LV）是TNBC中一种有效的凋亡诱导剂。从机制上讲，LV破坏了去泛素化酶USP14与关键抗凋亡蛋白Survivin之间的相互作用，增强了Survivin的多聚泛素化和蛋白酶体降解。发现USP14的过表达可稳定Survivin，并在体外和体内挽救LV诱导的凋亡和肿瘤抑制作用，而USP14的沉默或用IU1（一种USP14特异性抑制剂）抑制则增强了Survivin的周转，并与LV协同抑制TNBC细胞中的集落形成。通过生物信息学分析和免疫组织化学证明了临床相关性，揭示TNBC组织中Survivin表达升高与预后不良相关，并且在TNBC与非TNBC组织中显著上调。我们的研究结果确定USP14-Survivin轴为潜在的治疗靶点，并突出LV作为TNBC治疗的有希望的候选药物。
