β-hydroxybutyrate resensitizes colorectal cancer cells to oxaliplatin by suppressing H3K79 methylation in vitro and in vivo.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2024-06-23 DOI:10.1186/s10020-024-00864-1

Meng Deng, Peijie Yan, Hui Gong, Guiqiu Li, Jianjie Wang

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引用次数: 0

Abstract

Background: Ketone β-hydroxybutyrate (BHB) has been reported to prevent tumor cell proliferation and improve drug resistance. However, the effectiveness of BHB in oxaliplatin (Oxa)-resistant colorectal cancer (CRC) and the underlying mechanism still require further proof.

Methods: CRC-Oxa-resistant strains were established by increasing concentrations of CRC cells to Oxa. CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were checked following BHB intervention in vitro. The subcutaneous and metastasis models were established to assess the effects of BHB on the growth and metastasis of CRC-Oxa in vivo. Eight Oxa responders and seven nonresponders with CRC were enrolled in the study. Then, the serum BHB level and H3K79me, H3K27ac, H3K14ac, and H3K9me levels in tissues were detected. DOT1L (H3K79me methyltransferase) gene knockdown or GNE-049 (H3K27ac inhibitor) use was applied to analyze further whether BHB reversed CRC-Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vivo and in vitro.

Results: Following BHB intervention based on Oxa, the proliferation, migration, invasion, and EMT of CRC-Oxa cells and the growth and metastasis of transplanted tumors in mice were suppressed. Clinical analysis revealed that the differential change in BHB level was associated with drug resistance and was decreased in drug-resistant patient serum. The H3K79me, H3K27ac, and H3K14ac expressions in CRC were negatively correlated with BHB. Furthermore, results indicated that H3K79me inhibition may lead to BHB target deletion, resulting in its inability to function.

Conclusions: β-hydroxybutyrate resensitized CRC cells to Oxa by suppressing H3K79 methylation in vitro and in vivo.

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β-羟丁酸通过在体外和体内抑制 H3K79 甲基化，使结直肠癌细胞对奥沙利铂重新敏感。

背景：据报道，酮体β-羟丁酸（BHB）可防止肿瘤细胞增殖并改善耐药性。然而，BHB 对奥沙利铂（Oxa）耐药结直肠癌（CRC）的有效性及其内在机制仍有待进一步证实：方法：通过增加 CRC 细胞对 Oxa 的浓度建立 CRC-Oxa 耐药菌株。方法：通过增加 CRC 细胞对 Oxa 的浓度来建立 CRC-Oxa 耐药株，并在体外检测 BHB 干预后 CRC-Oxa 细胞的增殖、凋亡、侵袭、迁移和上皮-间质转化（EMT）。建立了皮下和转移模型，以评估 BHB 对体内 CRC-Oxa 生长和转移的影响。研究共纳入了 8 名 Oxa 反应者和 7 名非反应者。然后检测血清 BHB 水平和组织中的 H3K79me、H3K27ac、H3K14ac 和 H3K9me 水平。应用DOT1L（H3K79me甲基转移酶）基因敲除或GNE-049（H3K27ac抑制剂）进一步分析BHB在体内和体外是否通过H3K79去甲基化和/或H3K27去乙酰化逆转CRC-Oxa耐药性：结果：基于Oxa的BHB干预后，CRC-Oxa细胞的增殖、迁移、侵袭和EMT以及移植小鼠肿瘤的生长和转移均受到抑制。临床分析表明，BHB水平的不同变化与耐药性有关，耐药性患者血清中的BHB水平降低。CRC中H3K79me、H3K27ac和H3K14ac的表达与BHB呈负相关。结论：β-羟丁酸通过抑制体外和体内的 H3K79 甲基化使 CRC 细胞对 Oxa 再敏感。

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

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.