由于增强的糖酵解速率，癌细胞大量生成乳酸，随后促进组蛋白的乳酰化。尽管之前的研究已经探讨了组蛋白乳酰化在调节基因表达中的影响，但是这种表观遗传修饰在调控癌基因中的确切作用尚未完全明确。在本研究中，我们利用乳腺癌细胞系及其表现为乳酸缺乏代谢物质的突变体，发现增强的有氧糖酵解速率通过启动子水平的组蛋白乳酰化来支持c-Myc的表达。有趣的是，c-Myc进一步转录上调丝氨酸/精氨酸剪接因子10(SRSF10)，以促进乳腺癌细胞中MDM4和Bcl-x的选择性剪接。此外，我们的结果表明限制关键糖酵解酶的活性会影响c-Myc-SRSF10轴，从而抑制乳腺癌细胞的增殖。我们的发现为有氧糖酵解如何影响乳腺肿瘤发生过程中的选择性剪接提供了新的见解。此外，我们还预计，通过减弱糖酵解速率的化疗干预可以通过阻碍c-Myc-SRSF10轴来限制乳腺癌的进展。版权所有 © 2023. Elsevier Inc. 发布。

Due to the enhanced glycolytic rate, cancer cells generate lactate copiously, subsequently promoting the lactylation of histones. While previous studies have explored the impact of histone lactylation in modulating gene expression, the precise role of this epigenetic modification in regulating oncogenes is largely unchartered. In this study, using breast cancer cell lines and their mutants exhibiting lactate-deficient metabolome, we have identified that an enhanced rate of aerobic glycolysis supports c-Myc expression via promoter-level histone lactylation. Interestingly, c-Myc further transcriptionally upregulates serine/arginine splicing factor 10 (SRSF10) to drive alternative splicing of MDM4 and Bcl-x in breast cancer cells. Moreover, our results reveal that restricting the activity of critical glycolytic enzymes affects the c-Myc-SRSF10 axis to subside the proliferation of breast cancer cells. Our findings provide novel insights into the mechanisms by which aerobic glycolysis influences alternative splicing processes that collectively contribute to breast tumorigenesis. Furthermore, we also envisage that chemotherapeutic interventions attenuating glycolytic rate can restrict breast cancer progression by impeding the c-Myc-SRSF10 axis.Copyright © 2023. Published by Elsevier Inc.