Recent studies evidence that
ubiquitin-specific proteases (USPs) are associated with the occurrence and chemoresistance of T-cell
acute lymphoblastic leukemia (
T-ALL). N6 -methyladenosine (
m6A) demethylase AlkB homolog 5 (ALKBH5) exerts a carcinogenic effect in human
cancers and improves the mRNA stability of USPs. Whether
ubiquitin-specific protease 1 (USP1) controls chemoresistance of
T-ALL is unknown. Our study demonstrated that USP1 expression was upregulated in
glucocorticoid (GC)-resistant
T-ALL patients and cells (CEM-C1). High expression of USP1 was correlated to the poor prognosis in
T-ALL patients. Silencing USP1 increased CEM-C1 cell sensitivity to
dexamethasone (Dex), reduced cell invasion, promoted cell apoptosis, and ameliorated
glucocorticoid receptor (GR) expression. USP1 mediated
T-ALL chemoresistance by interacting with and deubiquitination of Aurora B. Overexpression of USP1 reversed the amelioration effect of Aurora B inhibitor on CEM-C1 cell resistance to Dex. Mechanistically, ALKBH5 enhanced USP1 expression by reducing
m6A level and mRNA stability in USP1
mRNA transcript. Downregulation of ALKBH5 reduced the levels of USP1 and Aurora B, facilitated CEM-C1 cell sensitivity to Dex, apoptosis, and GR expression, suppressed cell invasion. However, overexpression of USP1 reversed all the effects of ALKBH5 on CEM-C1 cells. In vivo results showed that tail vein injection of sh-USP1 resulted in a significant prolongation of mouse survival, suppressed
tumor growth, maintained the normal weight of mice, reduced USP1 expression and facilitated GR expression. In conclusion, inhibition of ALKBH5-mediated
m6A modification decreased USP1 expression and downregulation of USP1 ameliorated GC resistance of
T-ALL through suppressing Aurora B expression and elevating GR level.