Lactylation in cancer: Unveiling new layers of complexity

Since the debut of the Warburg effect, our understanding of lactate in cancer has evolved from a metabolic waste of "low-efficient" glucose metabolism, an acidification factor reshaping tumor microenvironments, to key molecular signals modulating signaling pathways, thereby influencing cell fates. Recently, Zhang’s work introduced a novel post-translational modification (PTM), lactylation, revealing a previously unidentified identity of lactate. Further findings in Plantae and Bacteria have projected lactylation as a common PTM among biological kingdoms.

Current lactylation writers can be categorized into lactyl-coenzyme A (CoA)-dependent or -independent manners (Figure 1, left). In the presence of lactyl-CoA, some histone acetyltransferases function as lactyltransferases, such as p300 and HBO1. They added lactyl lysine residues mainly in the promoter regions. Lactylation elevated the expression of METTL3 and "m6A reader" YTHDF2, indicating intricate lactylation regulation. This complexity of lactylation in gene expression regulation can be further highlighted by its impact on translational elongation and protein synthesis through lactylated EEF1A2 and on alternative splicing regulation by lactylated non-histone proteins such as Nucleolin. Furthermore, non-histone proteins lactylated by KAT5/TIP60 and CBP were involved in DNA damage response and chemotherapy resistance. These findings highlight a versatile regulatory mechanism of lactylation. These "non-lactylation-specific" writers and substrates project a potential sophisticated interaction with other types of PTMs, acting as context (e.g., cellular lactate level)-dependent orchestrators of cellular function.