AF9-KLF2基因调节回路将组蛋白乳酸化与代谢重编程和乳腺癌症进展联系起来
AF9-KLF2 gene regulatory circuit links histone lactylation to metabolic reprogramming and breast cancer progression.
摘要(中文译文)
组蛋白赖氨酸L-乳酸化（以下简称组蛋白Kla）是一种由糖酵解代谢诱导的染色质修饰，将代谢重编程与染色质介导的调控联系起来。在本研究中，我们揭示了一个涉及AF9和KLF2的转录调控回路，该回路驱动管腔型乳腺癌进展。AF9被鉴定为H3K9la的阅读器，促进KLF2表达，而KLF2作为AF9的转录因子，形成正反馈环路放大乳酸化依赖性效应。该回路激活肿瘤相关通路，包括TGF-β1、葡萄糖和乳酸转运体，以及糖酵解和丝氨酸生物合成所必需的代谢酶，驱动肿瘤发生。空间和单细胞转录组学显示，AF9阳性肿瘤细胞富集于乳酸化活跃区域，并与通过M2巨噬细胞相互作用实现的免疫逃逸相关。总之，AF9、H3K9la和KLF2整合代谢、染色质调控和信号传导以促进肿瘤进展，突显了AF9作为组蛋白乳酸化阅读器的核心作用及其作为乳腺癌潜在治疗靶点的价值。
Abstract
Histone lysine L-lactylation (hereafter referred to as histone Kla) is a chromatin modification induced by glycolytic metabolism, linking metabolic reprogramming and chromatin-mediated regulation. In this study, we uncover a transcriptional regulatory circuit involving AF9 and KLF2 that drives luminal breast cancer progression. AF9, identified as a reader of H3K9la, promotes KLF2 expression, while KLF2, functioning as a transcription factor for AF9, forms a positive feedback loop amplifying lactylation-dependent effects. This circuit activates tumor-associated pathways, including TGF-β1, glucose and lactate transporters, and metabolic enzymes essential for glycolysis and serine biosynthesis, driving tumorigenesis. Spatial and single-cell transcriptomics show AF9-positive tumor cells enriched in regions of active lactylation, correlating with immune evasion via M2 macrophage interactions. Together, AF9, H3K9la, and KLF2 integrate metabolism, chromatin regulation, and signaling to promote tumor progression, highlighting AF9's central role as a histone lactylation reader and potential therapeutic target in breast cancer.
如何引用
AMA
Huida Ma, Ming Yuan, Chenxuan Yang, Yuchen Yuan, Yuanyuan Li, Xin Wang, et al. AF9-KLF2 gene regulatory circuit links histone lactylation to metabolic reprogramming and breast cancer progression.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117429.
APA
Huida Ma, Ming Yuan, Chenxuan Yang, Yuchen Yuan, Yuanyuan Li, Xin Wang, et al (2026). AF9-KLF2 gene regulatory circuit links histone lactylation to metabolic reprogramming and breast cancer progression.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117429
GB/T 7714
Huida Ma, Ming Yuan, Chenxuan Yang, Yuchen Yuan, Yuanyuan Li, Xin Wang, et al. AF9-KLF2 gene regulatory circuit links histone lactylation to metabolic reprogramming and breast cancer progression.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117429.
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