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

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.