ALKBH5‐mediated m6A‐demethylation of USP1 regulated T‐cell acute lymphoblastic leukemia cell glucocorticoid resistance by Aurora B

Jun 25, 2021Molecular carcinogenesis

How ALKBH5 controls removal of m6A marks on USP1 to affect steroid resistance in T-cell acute lymphoblastic leukemia cells through Aurora B

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Abstract

USP1 expression was upregulated in glucocorticoid-resistant T-cell acute lymphoblastic leukemia patients and cells.

High levels of USP1 are correlated with poor prognosis in T-ALL patients.
Silencing USP1 increased sensitivity of CEM-C1 cells to dexamethasone, reduced invasion, and promoted apoptosis.
USP1 mediates chemoresistance by interacting with and deubiquitinating Aurora B.
ALKBH5 enhances USP1 expression by reducing m6A levels and increasing mRNA stability of USP1.
Downregulation of ALKBH5 decreased USP1 and Aurora B levels, improving CEM-C1 cell response to dexamethasone.

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Recent studies evidence that ubiquitin-specific proteases (USPs) are associated with the occurrence and chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL). N-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. 6

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ALKBH5‐mediated m6A‐demethylation of USP1 regulated T‐cell acute lymphoblastic leukemia cell glucocorticoid resistance by Aurora B

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