Dynamic regulation of H3K9 modifications in cancer: pathogenesis and targeted therapies

Post-translational modifications (PTMs) of histone H3 at lysine 9 (H3K9) contribute to chromatin homeostasis and transcriptional regulation and have been implicated in cancer progression. However, how distinct H3K9 modification states differ in function, compete for the same lysine residue, and dynamically respond to cellular context remains incompletely understood. This review summarizes the biochemical characteristics and enzymatic regulation of H3K9 methylation, acetylation, and non-acetyl acylations, including lactylation, β-hydroxybutyrylation, butyrylation, and crotonylation. We examine their roles in DNA replication, transcription, and DNA damage repair, as well as their interplay with other epigenetic regulatory mechanisms. We further discuss how H3K9-associated regulatory networks contribute to tumor proliferation, stemness maintenance, metabolic reprogramming, invasion and metastasis, immune microenvironment remodeling, therapeutic resistance, and programmed cell death, emphasizing their context-dependent and, in some settings, opposing biological effects. Finally, we evaluate preclinical and clinical advances in pharmacologically targeting H3K9-associated regulatory enzymes, distinguishing residue-specific mechanistic evidence from broader enzyme-level effects, and outline future directions for biomarker-guided epigenetic therapies in cancer.