9IM4

Crystal Structure of AF9 YEATS domain F28R mutant in complex with histone H3K9la

Summary for 9IM4

• Entry DOI: 10.2210/pdb9im4/pdb
• Descriptor: Protein AF-9, Histone H3.3C (3 entities in total)
• Functional Keywords: yeats domain, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 39463.32

Authors

Li, H.T.,Ma, H.D. (deposition date: 2024-07-02, release date: 2025-07-09, Last modification date: 2026-07-22)

Primary citation

Ma, H.,Yuan, M.,Yang, C.,Yuan, Y.,Li, Y.,Wang, X.,Tang, Z.,Li, H.
AF9-KLF2 gene regulatory circuit links histone lactylation to metabolic reprogramming and breast cancer progression.
Cell Rep, 45:117429-117429, 2026

PubMed 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.

PubMed: 42189684
DOI: 10.1016/j.celrep.2026.117429

Experimental method

X-RAY DIFFRACTION (2.794 Å)