PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6 [m6A-Seq]. PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6 [m6A-Seq]

Epigenetic modifications play important roles during the pathogenesis of multiple myeloma (MM). Here, we found that protein arginine methyltransferase 1 (PRMT1) was highly expressed in MM patients and its expression level was positively correlated with MM stages. High PRMT1 expression were notably related to adverse prognosis in MM patients. We further showed that silencing PRMT1 inhibited MM proliferation and tumorigenesis in vitro and in vivo. Mechanistically, we revealed that knockdown of PRMT1 reduced the oxidative phosphorylation (OXPHOS) of MM cells through downregulation of NDUFS6. Meanwhile, we identified that WTAP, a key component of the m6A methyltransferase complex, was methylated by PRMT1 and NDUFS6 was identified as a bona fide m6A target of WTAP. Finally, we found that PRMT1 inhibitor and bortezomib combination synergistically inhibited MM progression. Collectively, our results demonstrate that PRMT1 plays a crucial role during MM tumorigenesis and suggest that PRMT1 could be a potential therapeutic target in MM. Overall design: To identify the functional downstream target genes responsible for the observed phenotype, MM.1S cells knocked down for PRMT1 were used for m6A-Seq analyses.

表观遗传修饰（epigenetic modifications）在多发性骨髓瘤（multiple myeloma, MM）的发病进程中发挥关键作用。本研究发现，蛋白质精氨酸甲基转移酶1（protein arginine methyltransferase 1, PRMT1）在MM患者中呈高表达状态，且其表达水平与MM分期呈正相关。PRMT1高表达与MM患者的不良预后显著相关。我们进一步证实，敲低PRMT1可在体内外抑制MM细胞的增殖与致瘤能力。机制层面，本研究揭示，敲低PRMT1可通过下调NDUFS6的表达，降低MM细胞的氧化磷酸化（oxidative phosphorylation, OXPHOS）水平。同时，本研究证实，WTAP作为m6A甲基转移酶复合物（m6A methyltransferase complex）的核心组分，可被PRMT1催化甲基化，且NDUFS6是WTAP的真实m6A靶基因。最后，我们发现PRMT1抑制剂与硼替佐米（bortezomib）联合使用可协同抑制MM的疾病进展。综上，本研究结果表明PRMT1在MM的肿瘤发生过程中发挥至关重要的作用，提示PRMT1可作为MM潜在的治疗靶点。整体实验设计：为鉴定介导上述观测表型的功能性下游靶基因，本研究采用敲低了PRMT1的MM.1S细胞进行m6A-Seq分析。