ZNF480 Accelerates Chemotherapy Resistance in Breast Cancer by Competing With TRIM28 and Stabilizing LSD1 to Upregulate the AKT-GSK3β-Snail Pathway.

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-11-06 DOI:10.1002/mc.23837
Xiaowen Ma, Yufeng Jiang, Hangqi Zhao, Yusong Qiu, Zhijian Liu, Xiupeng Zhang, Mingwei Fan, Yong Zhang, Yue Zhang
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Abstract

Zinc finger protein 480 (ZNF480) may interact with lysine-specific demethylase 1 (LSD1), which is highly expressed in many malignant tumors; however, ZNF480 expression has not previously been investigated in breast cancer. Therefore, we explored the expression and molecular mechanisms of ZNF480 in breast cancer. According to public databases and immunohistochemical staining analysis, ZNF480 is highly expressed in the tissue of patients with breast cancer, and ZNF480 expression is positively correlated with advanced TNM stage (p = 0.036), lymph node metastasis (p = 0.012), and poor prognosis (p = 0.005). ZNF480 overexpression enhances breast cancer cell proliferation, migration, and stemness by activating AKT-GSK3β-Snail signaling both in vitro and in vivo. Moreover, ZNF480 binds to LSD1 through its KRAB domain, thereby activating AKT signaling. Mass spectrometry and co-immunoprecipitation revealed that ZNF480 abrogates ubiquitination degradation and subsequently stabilizes LSD1 through competitive binding with TRIM28. Ipragliflozin was identified as a small-molecule inhibitor of ZNF480 and LSD1 interaction that may block breast cancer progression. Moreover, ZNF480 expression was significantly higher in treatment-resistant patients than in treatment-sensitive patients. Thus, ipragliflozin may neutralize neoadjuvant chemotherapy resistance induced by ZNF480 overexpression. Overall, elevated ZNF480 expression is positively associated with poor patient outcomes. Mechanistically, ZNF480 accelerates proliferation and neoadjuvant chemotherapy resistance in breast cancer cells via the AKT-GSK3β-Snail pathway by interacting with and stabilizing LSD1 in a competitive manner within TRIM28. This research has implications for developing targeted drugs against chemotherapy resistance in breast cancer.

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ZNF480通过与TRIM28竞争和稳定LSD1上调AKT-GSK3β-Snail通路加速乳腺癌的化疗耐药性
锌指蛋白480(ZNF480)可能与赖氨酸特异性去甲基化酶1(LSD1)相互作用,而LSD1在许多恶性肿瘤中都有高表达;然而,ZNF480在乳腺癌中的表达以前还没有研究过。因此,我们探讨了 ZNF480 在乳腺癌中的表达和分子机制。根据公共数据库和免疫组化染色分析,ZNF480在乳腺癌患者组织中高表达,ZNF480的表达与TNM分期晚期(p = 0.036)、淋巴结转移(p = 0.012)和预后不良(p = 0.005)呈正相关。ZNF480 在体外和体内通过激活 AKT-GSK3β-Snail 信号增强了乳腺癌细胞的增殖、迁移和干性。此外,ZNF480通过其KRAB结构域与LSD1结合,从而激活AKT信号。质谱分析和共免疫沉淀显示,ZNF480通过与TRIM28竞争性结合,可抑制泛素化降解,进而稳定LSD1。Ipragliflozin被鉴定为ZNF480和LSD1相互作用的小分子抑制剂,可阻止乳腺癌的进展。此外,ZNF480在耐药患者中的表达明显高于对治疗敏感的患者。因此,ipragliflozin可中和ZNF480过表达引起的新辅助化疗耐药性。总体而言,ZNF480表达的升高与患者的不良预后呈正相关。从机理上讲,ZNF480通过与TRIM28中的LSD1相互作用并以竞争方式稳定LSD1,从而通过AKT-GSK3β-Snail通路加速乳腺癌细胞的增殖和新辅助化疗耐药。这项研究对开发针对乳腺癌化疗耐药性的靶向药物具有重要意义。
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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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