USP30 promotes cytarabine resistance in acute myeloid leukemia by deubiquitinating and stabilizing FOXM1.

Acute myeloid leukemia (AML) is a hematologic malignancy. Cytarabine (Ara-C) is a key drug in its chemotherapy, yet the development of drug resistance remains a major cause of treatment failure. Ubiquitin specific peptidase 30 (USP30) and forkhead box M1 (FOXM1) have been implicated in the progression of AML, yet the mutual regulatory mechanism between them remains unclear. Western blot was employed to assess the protein expression of USP30 and FOXM1 in tissues and cells. Cell proliferation and cell cycle were evaluated by EdU and flow cytometry assays. Cell apoptosis was determined using flow cytometry and TUNEL assays. The UbiBrowser 2.0, Co-IP, and cycloheximide (CHX) assays were applied to assess the interaction between USP30 and FOXM1. Subsequently, Ara-C-resistant cell lines and animal models were established, and immunohistochemistry (IHC) was performed to analyze Ki-67 and USP30 expression in tumor tissues from mice. The results showed that USP30 and FOXM1 were highly expressed in AML. Knockdown of USP30 repressed cell proliferation and cell cycle progression and promoted cell apoptosis. Additionally, USP30 stabilized FOXM1 protein expression through its deubiquitination activity. FOXM1 overexpression reversed the impacts of USP30 silencing on proliferation, cell cycle, and apoptosis in AML cells. Furthermore, USP30 enhanced Ara-C resistance in AML cells in vivo. Together, USP30 promoted Ara-C resistance in AML by deubiquitinating and stabilizing FOXM1, thereby enhancing tumor growth and cell survival.