YEATS2: a novel cancer epigenetic reader and potential therapeutic target

YEATS2, an evolutionarily conserved reader of histone acylation marks (H3K27ac, H3K27cr, H3K27bz), functions as a central oncogenic driver in diverse cancers, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC). Its structurally plastic YEATS domain bridges acyl-CoA metabolism to chromatin remodeling, amplifying transcription of survival genes such as MYC, BCL2, and PD-L1. YEATS2 orchestrates malignancy-specific programs—sustaining ribosome biogenesis in NSCLC through ATAC complex recruitment, enhancing NF-κB-dependent immune evasion in PDAC, and activating PI3K/AKT-driven metabolic rewiring in HCC. Structural studies demonstrate a unique aromatic cage architecture that selectively engages diverse acylated histones. Although pyrazolopyridine-based inhibitors targeting the YEATS domain show preclinical efficacy, developing isoform-selective agents remains challenging. Clinically, YEATS2 overexpression correlates with therapy resistance and may synergize with immune checkpoint blockade. This review integrates mechanistic insights into the role of YEATS2 in epigenetic regulation, evaluates its therapeutic potential, and proposes future directions: elucidating full-length complex topologies, mapping synthetic lethal interactors, and optimizing selective inhibitors. Disrupting YEATS2-mediated epigenetic adaptation presents novel opportunities for precision cancer therapy.