Page 7 - 南京医科大学自然版

第45卷第7期 南京医科大学学报（自然科学版）
2025年7月 Journal of Nanjing Medical University（Natural Sciences） ·905 ·

·专题研究：乳腺癌·

IGF2BP3 通过 m6A⁃EP300 轴介导乳酸化修饰驱动三阴性乳腺

癌代谢与表观遗传交互作用

李逸涵，王子文，陈 锐，杨海燕，蔡梦媛，李驿洵，吴柯非，王雨欣，丁 强 *

南京医科大学第一附属医院乳腺病中心，江苏 南京 210029

［摘 要］ 目的：探讨乳酸对三阴性乳腺癌（triple⁃negative breast cancer，TNBC）细胞恶性行为的影响，并揭示胰岛素样生长因
子 2 mRNA 结合蛋白 3（insulin⁃like growth factor 2 mRNA binding protein 3，IGF2BP3）通过 m6A 依赖性方式调控 EP300，进而介
导代谢重编程的表观遗传学机制。方法：通过外源性添加乳酸钠处理TNBC细胞，采用CCK⁃8、集落形成、划痕愈合和Transwell
实验检测细胞增殖与迁移能力；利用shRNA慢病毒载体构建IGF2BP3稳定敲低细胞模型，结合Western blot分析组蛋白乳酸化
修饰水平；进一步通过 RIP⁃seq、MeRIP⁃seq 筛选 IGF2BP3 的 m6A 靶基因，并利用 qRT⁃PCR 和 Western blot 验证关键分子表达。
结果：乳酸钠处理显著增强了TNBC细胞的增殖和迁移能力，且泛乳酸化水平随乳酸浓度梯度升高而增加。IGF2BP3敲低可降
低组蛋白乳酸化修饰水平。通过整合 RIP⁃seq 和 MeRIP⁃seq 数据，鉴定出 699 个其转录本同时被 IGF2BP3 特异性结合且携带
m6A修饰的候选基因，这些基因显著富集于表观遗传调控和代谢相关通路。EP300转录本上IGF2BP3的结合区域与m6A修饰
位点高度重合，且EP300的表达水平在IGF2BP3敲低后明显下调。结论：外源性乳酸通过泛乳酸化修饰促进TNBC的恶性进
展。IGF2BP3通过m6A依赖性机制调控EP300的表达，进而介导组蛋白乳酸化修饰与代谢重编程的协同作用，最终驱动TNBC
的肿瘤进展。上述发现为靶向代谢⁃表观遗传交互调控的新型治疗策略提供了理论依据。
［关键词］ 三阴性乳腺癌；乳酸；IGF2BP3；EP300
［中图分类号］ R737.9 ［文献标志码］ A ［文章编号］ 1007⁃4368（2025）07⁃905⁃08
doi：10.7655/NYDXBNSN250474

IGF2BP3 drives the metabolic ⁃ epigenetic crosstalk in triple ⁃ negative breast cancer
through m6A⁃EP300 axis⁃mediated lactylation modification

LI Yihan，WANG Ziwen，CHEN Rui，YANG Haiyan，CAI Mengyuan，LI Yixun，WU Kefei，WANG Yuxin，
DING Qiang *
Breast Disease Center，the First Affiliated Hospital of Nanjing Medical University，Nanjing 210029，China

［Abstract］ Objective：To investigate the functional impact of lactate on triple ⁃ negative breast cancer（TNBC）malignancy and
elucidate an m6A⁃dependent epigenetic mechanism through which insulin⁃like growth factor 2 mRNA⁃binding protein 3（IGF2BP3）

orchestrates metabolic reprogramming via regulation of EP300. Methods：TNBC cells were treated with exogenous sodium lactate
supplementation to investigate their oncogenic effects. Cell proliferation and migration were assessed via CCK⁃8，colony formation，
wound healing，and Transwell assays. Stable IGF2BP3⁃knockdown cell models were established using shRNA lentiviral vectors，with
histone lactylation modification levels analyzed by Western blot. RNA immunoprecipitation sequencing（RIP⁃seq）and m6A⁃specific
methylated RNA immunoprecipitation sequencing（MeRIP⁃seq）were used to identify IGF2BP3’s m6A target genes，validated by qRT⁃
PCR and Western blot for key molecule expression. Results：Sodium lactate treatment significantly enhanced TNBC cell proliferation
and migration，with pan⁃lactylation levels increasing dose⁃dependently. IGF2BP3 knockdown reduced histone lactylation. Integrated
RIP ⁃ seq/MeRIP ⁃ seq analysis identified 699 candidate genes whose transcripts bore both IGF2BP3 ⁃ specific binding and m6A
modifications，significantly enriched in epigenetic regulation and metabolic pathways. IGF2BP3⁃binding regions on EP300 transcripts
overlapped extensively with m6A sites，and EP300 expression was markedly downregulated post⁃IGF2BP3 knockdown. Conclusion：

［基金项目］ 江苏省科技重大专项（BG2024026）
通信作者（Corresponding author），E⁃mail：dingqiang@njmu.edu.cn（ORCID：0000⁃0003⁃1499⁃6200）
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