UNASSIGNED: Lactylation and METTL3 expression levels in ATRA-sensitive and ATRA-resistant APL cells were detected by Western blot analysis, qRT-PCR and CO-IP. Flow cytometry (FCM) and APL xenograft mouse models were used to determine the effect of METTL3 and GRh2 on ATRA-resistance.
UNASSIGNED: Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3.
UNASSIGNED: This study suggests that lactylation-modified METTL3 could provide a promising strategy for ameliorating ATRA-resistance in APL, and GRh2 could act as a potential lactylation-modified METTL3 inhibitor to ameliorate ATRA-resistance in APL.
■通过蛋白质印迹分析检测ATRA敏感和抗ATRA的APL细胞中的Lactylation和METTL3表达水平,qRT-PCR和CO-IP。使用流式细胞术(FCM)和APL异种移植小鼠模型来确定METTL3和GRh2对ATRA抗性的影响。
■在抗ATRA的APL细胞中组蛋白乳化作用和METTL3表达水平显著上调。METTL3受组蛋白乳酸化和直接乳酸化修饰调控。METTL3的过表达促进ATRA抗性。GRh2通过下调乳酸化水平和直接抑制METTL3改善ATRA抗性。
■这项研究表明,乳酸盐修饰的METTL3可以为改善APL中的ATRA抗性提供有希望的策略,和GRh2可以作为一种潜在的乳酸化修饰的METTL3抑制剂,以改善APL中的ATRA耐药性。