Lactylation: A novel metabolic–epigenetic link in pancreatic cancer
TL;DR
This comprehensive review examines the intricate mechanisms governing lactylation, its widespread presence across the proteome, and its specific roles in cancer pathogenesis, with a particular emphasis on pancreatic ductal adenocarcinoma (PDAC).
Abstract
Lactylation, a recently discovered post-translational modification, represents a crucial nexus between cellular metabolism and epigenetic regulation. Driven by the accumulation of lactate, a byproduct of glycolysis, this modification involves the covalent attachment of a lactyl group to lysine residues on both histone and non-histone proteins. Emerging evidence highlights the profound impact of lactylation on various biological processes, including gene expression, cell proliferation, migration, invasion, autophagy, and immune responses, particularly in cancer. This comprehensive review examines the intricate mechanisms governing lactylation, its widespread presence across the proteome, and its specific roles in cancer pathogenesis, with a particular emphasis on pancreatic ductal adenocarcinoma (PDAC). We explore how lactylation at histone H3 lysine 18 (H3K18la), histone H4 lysine 12 (H4K12la), and histone H3 lysine (H3K9la) influences chromatin accessibility and gene transcription, thereby shaping tumor characteristics. Furthermore, we examine the diverse functions of non-histone protein lactylation in regulating metabolic pathways, immune evasion, epithelial–mesenchymal transition, and ferroptosis. The review also discusses the diagnostic and prognostic potential of lactylation markers in PDAC and evaluates the therapeutic implications of targeting lactylation pathways to overcome drug resistance and inhibit tumor progression. By consolidating current knowledge, this review underscores lactylation as a pivotal regulatory layer in cancer biology, offering novel avenues for therapeutic intervention.