20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3

IF 6.8 2区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Ginseng Research Pub Date : 2023-12-27 DOI:10.1016/j.jgr.2023.12.003

Siyu Cheng , Langqun Chen , Jiahui Ying , Ying Wang , Wenjuan Jiang , Qi Zhang , Hong Zhang , Jiahe Wang , Chen Wang , Huimin Wu , Jing Ye , Liang Zhang

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引用次数: 0

Abstract

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.

Abstract Image

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20(S)-人参皂苷Rh2通过调节乳化驱动的METTL3，改善APL对ATRA的耐药性

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，可抑制急性髓性白血病（AML）细胞增殖。乳酸调控组蛋白乳酰化，其时间动态与乙酰化不同。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酸化修饰是否与全反式维甲酸（ATRA）抗性有关，目前尚未见报道。方法通过 Western 印迹分析、qRT-PCR 和 CO-IP 检测 ATRA 敏感和 ATRA 抗性 APL 细胞中乳化和 METTL3 的表达水平。结果组蛋白乳化和METTL3表达水平在ATRA耐药的APL细胞中显著上调。METTL3受组蛋白乳化和直接乳化修饰的调控。METTL3的过表达促进了对ATRA的耐药性。结论这项研究表明，乳化修饰的METTL3可为改善APL的ATRA耐药性提供一种有前景的策略，而GRh2可作为一种潜在的乳化修饰METTL3抑制剂来改善APL的ATRA耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Ginseng Research CHEMISTRY, MEDICINAL-INTEGRATIVE & COMPLEMENTARY MEDICINE

CiteScore

11.40

自引率

9.50%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Journal of Ginseng Research (JGR) is an official, open access journal of the Korean Society of Ginseng and is the only international journal publishing scholarly reports on ginseng research in the world. The journal is a bimonthly peer-reviewed publication featuring high-quality studies related to basic, pre-clinical, and clinical researches on ginseng to reflect recent progresses in ginseng research. JGR publishes papers, either experimental or theoretical, that advance our understanding of ginseng science, including plant sciences, biology, chemistry, pharmacology, toxicology, pharmacokinetics, veterinary medicine, biochemistry, manufacture, and clinical study of ginseng since 1976. It also includes the new paradigm of integrative research, covering alternative medicinal approaches. Article types considered for publication include review articles, original research articles, and brief reports. JGR helps researchers to understand mechanisms for traditional efficacy of ginseng and to put their clinical evidence together. It provides balanced information on basic science and clinical applications to researchers, manufacturers, practitioners, teachers, scholars, and medical doctors.