NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma

Multiple myeloma(MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10(NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing(ac RIP-seq) and ribosome profiling sequencing(Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170(CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover,CEP170 overexpression promoted cellular proliferation and chromosomal instability(CIN) in MM.Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP170 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.

BUB1B and circBUB1B_544aa aggravate multiple myeloma malignancy through evoking chromosomal instability

Multiple myeloma(MM)is an incurable plasma cell malignancy in the bone marrow characterized by chromosome instability(CIN),which contributes to the acquisition of heterogeneity,along with MM progression,drug resistance,and relapse.In this study,we elucidated that the expression of BUB1B increased strikingly in MM patients and was closely correlated with poor outcomes.Overexpression of BUB1B facilitated cellular proliferation and induced drug resistance in vitro and in vivo,while genetic targeting BUB1B abrogated this effect.Mechanistic studies unveiled that enforced expression of BUB1B evoked CIN resulting in MM poor outcomes mainly through phosphorylating CEP170.Interestingly,we discovered the existence of circBUB1B_544aa containing the kinase catalytic center of BUB1B,which was translated by a circular RNA of BUB1B.The circBUB1B_544aa elevated in MM peripheral blood samples was closely associated with MM poor outcomes and played a synergistic effect with BUB1B on evoking CIN.In addition,MM cells could secrete circBUB1B_544aa and interfere the MM microenvironmental cells in the same manner as BUB1B full-length protein.Intriguingly,BUB1B siRNA,targeting the kinase catalytic center of both BUB1B and circBUB1B_544aa,significantly inhibited MM malignancy in vitro and in vivo.Collectively,BUB1B and circBUB1B_544aa are promising prognostic and therapeutic targets of MM.