乳腺癌是全世界最常见的女性恶性肿瘤。泛素特异性肽酶 53 (USP53) 已被证明在多种实体瘤中发挥癌症抑制功能，但其在乳腺癌中的作用和潜在机制尚未明确阐明。因此，我们在生物信息学、临床组织、细胞功能和动物模型等层面对此事进行了一系列详细的研究。我们发现乳腺癌标本中USP53表达下调，且与临床分期呈负相关。功能获得和丧失实验表明，USP53 抑制乳腺癌细胞的增殖、克隆形成、细胞周期和异种移植物生长，并诱导细胞凋亡和线粒体损伤。免疫共沉淀数据表明，USP53 与锌指 MYND 型含 11 (ZMYND11) 相互作用，并催化其去泛素化和稳定化。 33-50 个氨基酸的 Cys-box 结构域是 USP53 酶活性的关键，但对于其与 ZMYND11 的结合并不是必需的。挽救实验表明，USP53在乳腺癌细胞中的抗肿瘤作用至少部分是由ZMYND11介导的。 USP53和ZMYND11都是乳腺癌的预后保护因素。 USP53-ZMYND11 轴可能是乳腺癌的一个良好的潜在生物标志物或治疗靶点，可以为诊断、治疗和预后提供新的见解。© 2024。作者。

Breast cancer is the most common female malignancy worldwide. Ubiquitin-specific peptidase 53 (USP53) has been shown to exert cancer-suppressing functions in several solid tumors, but its role and the underlying mechanism in breast cancer has not been clearly elucidated. Therefore, we have carried out a series of detailed studies on this matter at the levels of bioinformatics, clinical tissue, cell function and animal model. We found that USP53 expression was downregulated in breast cancer specimens and was negatively correlated with the clinical stages. Gain- and loss-of-function experiments demonstrated USP53 inhibited proliferation, clonogenesis, cell cycle and xenograft growth, as well as induced apoptosis and mitochondrial damage of breast cancer cells. Co-immunoprecipitation data suggested that USP53 interacted with zinc finger MYND-type containing 11 (ZMYND11), and catalyzed its deubiquitination and stabilization. The 33-50 amino acid Cys-box domain was key for USP53 enzyme activity, but not essential for its binding with ZMYND11. The rescue experiments revealed that the anti-tumor role of USP53 in breast cancer cells was at least partially mediated by ZMYND11. Both USP53 and ZMYND11 were prognostic protective factors for breast cancer. USP53-ZMYND11 axis may be a good potential biomarker or therapeutic target for breast cancer, which can provide novel insights into the diagnosis, treatment and prognosis.© 2024. The Author(s).