20(S)-人参皂苷Rh2通过调节乳酰化驱动的METTL3改善急性早幼粒细胞白血病中的全反式维甲酸耐药性。
20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3.
作者信息
Cheng Siyu, Chen Langqun, Ying Jiahui, Wang Ying, Jiang Wenjuan, Zhang Qi, Zhang Hong, Wang Jiahe, Wang Chen, Wu Huimin, Ye Jing, Zhang Liang
机构信息
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
出版信息
J Ginseng Res. 2024 May;48(3):298-309. doi: 10.1016/j.jgr.2023.12.003. Epub 2023 Dec 27.
BACKGROUND
20(S)-ginsenoside Rh2(GRh2), an effective natural histone deacetylase inhibitor, can inhibit acute myeloid leukemia (AML) cell proliferation. Lactate regulated histone lactylation, which has different temporal dynamics from acetylation. However, whether the high level of lactylation modification that we first detected in acute promyelocytic leukemia (APL) is associated with all-trans retinoic acid (ATRA) resistance has not been reported. Furthermore, Whether GRh2 can regulate lactylation modification in ATRA-resistant APL remains unknown.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
背景
20(S)-人参皂苷Rh2（GRh2）是一种有效的天然组蛋白去乙酰化酶抑制剂，可抑制急性髓系白血病（AML）细胞增殖。乳酸调节组蛋白乳酰化，其具有与乙酰化不同的时间动态。然而，我们首次在急性早幼粒细胞白血病（APL）中检测到的高水平乳酰化修饰是否与全反式维甲酸（ATRA）耐药相关尚未见报道。此外，GRh2是否能调节ATRA耐药的APL中的乳酰化修饰仍不清楚。
方法
采用蛋白质免疫印迹分析、qRT-PCR和免疫共沉淀法检测ATRA敏感和ATRA耐药的APL细胞中的乳酰化和METTL3表达水平。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耐药性的影响。
结果
在ATRA耐药的APL细胞中，组蛋白乳酰化和METTL3表达水平显著上调。METTL3受组蛋白乳酰化和直接乳酰化修饰的调节。METTL3的过表达促进了ATRA耐药。GRh2通过下调乳酰化水平和直接抑制METTL3改善了ATRA耐药。
结论
本研究表明，乳酰化修饰的METTL3可能为改善APL中的ATRA耐药提供一种有前景的策略，并且GRh2可作为一种潜在的乳酰化修饰的METTL3抑制剂来改善APL中的ATRA耐药。
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