目的:多发性骨髓瘤(MM)是一种致命的浆细胞恶性肿瘤,其发病机制难以捉摸。N6-甲基腺苷(m6A)严重参与血液恶性肿瘤。甲基转移酶的最大成分KIAA1429的功能,是未知的。本研究探讨了KIAA1429在MM中的作用机制,希望为MM治疗提供新的靶点。
方法:从55例MM患者和15例对照中获取骨髓样本。检测KIAA1429、YTHDF1和FOXM1mRNA水平并分析其相关性。细胞活力,扩散,细胞周期,细胞凋亡得到证实。糖酵解增强基因(HK2、ENO1和LDHA),乳酸生产,和葡萄糖摄取进行评估。FOXM1mRNA与YTHDF1,m6A修饰的FOXM1水平之间的相互作用,和FOXM1稳定性进行了测定。建立移植瘤模型以证实KIAA1429的机制。
结果:KIAA1429在MM患者和MM细胞中处于高水平,并与不良预后相关。KIAA1429敲低克制MM细胞活力,和扩散,被捕G0/G1期,和增加细胞凋亡。MM患者浆细胞中的KIAA1429mRNA与糖酵解增强基因呈正相关。糖酵解增强基因的水平,葡萄糖摄取,在KIAA1429敲除后,乳酸的产生受到抑制,随着降低FOXM1水平和稳定性。YTHDF1识别KIAA1429甲基化FOXM1mRNA并提高FOXM1稳定性。敲除YTHDF1抑制MM细胞的有氧糖酵解和恶性行为,FOXM1过表达无效。在动物实验中,KIAA1429敲低也抑制肿瘤生长。
结论:KIAA1429敲低通过YTHDF1介导的m6A修饰降低FOXM1表达,从而抑制MM有氧糖酵解和肿瘤发生。
OBJECTIVE: Multiple myeloma (MM) is a deadly plasma cell malignancy with elusive pathogenesis. N6-methyladenosine (m6A) is critically engaged in hematological malignancies. The function of KIAA1429, the largest component of methyltransferases, is unknown. This study delved into the mechanism of KIAA1429 in MM, hoping to offer novel targets for MM therapy.
METHODS: Bone marrow samples were attained from 55 MM patients and 15 controls. KIAA1429, YTHDF1, and FOXM1 mRNA levels were detected and their correlation was analyzed. Cell viability, proliferation, cell cycle, and apoptosis were testified. Glycolysis-enhancing genes (HK2, ENO1, and LDHA), lactate production, and glucose uptake were evaluated. The interaction between FOXM1 mRNA and YTHDF1, m6A-modified FOXM1 level, and FOXM1 stability were assayed. A transplantation tumor model was built to confirm the mechanism of KIAA1429.
RESULTS: KIAA1429 was at high levels in MM patients and MM cells and linked to poor prognoses. KIAA1429 knockdown restrained MM cell viability, and proliferation, arrested G0/G1 phase, and increased apoptosis. KIAA1429 mRNA in plasma cells from MM patients was positively linked with to glycolysis-enhancing genes. The levels of glycolysis-enhancing genes, glucose uptake, and lactate production were repressed after KIAA1429 knockdown, along with reduced FOXM1 levels and stability. YTHDF1 recognized KIAA1429-methylated FOXM1 mRNA and raised FOXM1 stability. Knockdown of YTHDF1 curbed aerobic glycolysis and malignant behaviors in MM cells, which was nullified by FOXM1 overexpression. KIAA1429 knockdown also inhibited tumor growth in animal experiments.
CONCLUSIONS: KIAA1429 knockdown reduces FOXM1 expression through YTHDF1-mediated m6A modification, thus inhibiting MM aerobic glycolysis and tumorigenesis.