NAT10 Mediates XPO1 mRNA N4-acetylation and Promotes Drug Resistance of Myeloma Cells.

Abstract

The eventually developed chemoresistance to proteasome inhibitors (PIs) is a major hurdle in curing patients with multiple myeloma (MM) and a key cause of poor prognosis, however the underlying molecular mechanisms of chemoresistance is still poorly understood. Herein, we provide evidences that N-acetyltransferase 10 (NAT10), a catalytic enzyme involving in the acetylation modification of RNA, is overexpressed in the BTZ-resistant (BR) MM cell lines and predicts poor outcomes in the clinic. Further manipulating of NAT10 gene expression in MM cells shows that enforced NAT10 expression decreases sensitivity to PI, however knockdown of NAT10 enhances anti-tumor efficacy of PIs in MM cells in vitro and in vivo. Acetylated RNA immunoprecipitation sequencing (acRIP-seq) combined with RIP-qPCR analysis identifies exportin 1 (XPO1) as an important downstream target of NAT10, with promotes N4-acetylcytidine (ac4C) modification of XPO1 mRNA. Importantly, expressions of XPO1 and NAT10 are meaningfully correlated in bone biopsies from the relapsed/refractory (R/R) MM patients, which were also highly associated with poor outcome. Translationally, dual pharmacological inhibition of NAT10 and XPO1 sensitizes MM cells to BTZ treatment in both cell lines and in a xenograft mouse model of MM. Thus, our study elucidates previously unrecognized role of ac4C modification of XPO1 mRNA in the chemoresistance of MM and provides a potential option for clinical management of R/R MM patients in the clinic.