Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription

Abstract

Heightened lactate production in cancer cells has been linked to various cellular mechanisms such as angiogenesis, hypoxia, macrophage polarisation and T-cell dysfunction. The lactate-induced lactylation of histone lysine residues is noteworthy, as it functions as an epigenetic modification that directly augments gene transcription from chromatin. This epigenetic modification originating from lactate effectively fosters a reliance on transcription, thereby expediting tumour progression and development. Herein, this review explores the correlation between histone lactylation and cancer characteristics, revealing histone lactylation as an innovative epigenetic process that enhances the vulnerability of cells to malignancy. Moreover, it is imperative to acknowledge the paramount importance of acknowledging innovative therapeutic methodologies for proficiently managing cancer by precisely targeting lactate signalling. This comprehensive review illuminates a crucial yet inadequately investigated aspect of histone lactylation, providing valuable insights into its clinical ramifications and prospective therapeutic interventions centred on lactylation.

Keywords: cancer; histone lactylation; metabolic reprogramming.

FIGURE 1

The correlation between histone lactylation and the interconnection of epigenetic remodelling and metabolic reprogramming during the progression of cancerous development. Metabolic disorders are visually represented in red, while epigenetic rewiring is depicted in green.

FIGURE 2

The illustration of the Warburg effect elicits an elevation in lactate levels, which is associated with multiple cancer‐related traits inclding enhanced signalling for cell proliferation, evasion of growth inhibitory factors, activation of invasion and metastasis, heightened capacity for angiogenesis, evasion of immune system destruction and facilitation of replicative immortality.

FIGURE 3

Oncogenic functions of histone lactylation in metabolic reprogramming, immunological remodelling, cell senescence and stemness maintenance.

FIGURE 4

Examples of targeting lactate metabolism in cancer treatment, including neuroblastoma, lung cancer, hepatocellular carcinoma, etc.