NAT10 acetylates BCL-XL mRNA to promote the proliferation of multiple myeloma cells through PI3K-AKT pathway

Abstract

Multiple myeloma (MM) is a clinically distinctive plasma cell malignancy in the bone marrow (BM), in which epigenetic abnormalities are featured prominently. Epigenetic modifications including acetylation have been deemed to contribute to tumorigenesis. N-acetyltransferase 10 (NAT10) is an important regulator of mRNA acetylation in many cancers, however its function in MM is poorly studied. We first analyzed MM clinical databases and found that elevated NAT10 expression conferred a poor prognosis in MM patients. Furthermore, overexpression of NAT10 promoted MM cell proliferation. The correlation analysis of acRIP-seq screened BCL-XL (BCL2L1) as a significant downstream target of NAT10. Further RNA decay assay showed that increased NAT10 improved the stability of BCL-XL mRNA and promoted protein translation to suppress cell apoptosis. NAT10 activated PI3K-AKT pathway and upregulated CDK4/CDK6 to accelerate cellular proliferation. Importantly, inhibition of NAT10 by Remodelin suppressed MM cell growth and induced cell apoptosis. Our findings show the important role of NAT10/BCL-XL axis in promoting MM cell proliferation. Further explorations are needed to fully define the potential of targeting NAT10 therapy in MM treatment.

Mechanisms of NAT10 as ac4C writer in diseases

“…The mRNA acetylation regulator NAT10 improves translation efficiency in cells, which in turn stimulates cell growth. 55 CEP170 is a centrosomal protein that promotes the development and spread of cancer, which was stabilized and its translation efficiency was increased due to high expression of NAT10 and enrichment of ac4C acetylation levels at the C terminus of the mRNA encoding CEP170. 56 , 57 , 58 Notably, mitosis relies on NAT10, 59 , 60 which is connected with the nuclear membrane and plays a significant role in cell division.…”

“…Increasing expression of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) and a reduction in the G0/G1 phase have been linked to NAT10 overexpression in MM cells. Likewise, upstream p-AKT is enhanced to activate the PI3K-AKT pathway and promote MM cell proliferation, 55 yet increasing anti-apoptotic BCL-XL suppresses the downstream apoptotic protein BAX.…”

NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma

“…Mechanistically, NAT10 enhances oncogenic mRNA stability and translation in pancreatic ductal adenocarcinoma by remodeling ac4C modified mRNAs [ 22 ]. In multiple myeloma cells, NAT10 acetylates and stabilizes BCL-XL mRNA, which leads to elevated expression of BCL-XL, inhibiting apoptosis and activating the PI3K-AKT pathway, thereby promoting cell cycle progression and proliferation during multiple myeloma malignancy [ 26 ]. Furthermore, NAT10 directly controls the expression of RUNX2 through ac4C modification, regulating osteoblast differentiation ability of BMSC in vitro; thus, it can be used as a new potential therapeutic target for osteoporosis [ 27 ].…”

Network pharmacology- and molecular docking-based investigation of the therapeutic potential and mechanism of daucosterol against multiple myeloma

“…PRKAB1 participates in the AMPK pathway, and the activation of AMPK pathway is associated with survival of MM cells ( 67 ). PRKAA1 is involved in PI3K-Akt signaling pathway, and the activated PI3K-AKT pathway could accelerate cellular proliferation of MM ( 68 ). Studies have shown that daucosterol could significantly increase the levels of GSK3B , PRKAA1 , and PRKAB1 , and promote the inducting of GSK3-beta phosphorylation and AMPK phosphorylation respectively ( 69 ).…”