Lactate‐induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer

Abstract

Lactate is not only an endpoint of glycolysis but is gradually being discovered to play the role of a universal metabolic fuel for energy via the ‘lactate shuttle’ moving between cells and transmitting signals. The glycolytic‐dependent metabolism found in tumours and fast‐growing cells has made lactate a pivotal player in energy metabolism reprogramming, which enables cells to obtain abundant energy in a short time. Moreover, lactate can provide favourable conditions for tumorigenesis by shaping the acidic tumour microenvironment, recruiting immune cells, etc. and the recently discovered lactate‐induced lactylation moves even further on pro‐tumorigenesis mechanisms of lactate production, circulation and utilization. As with other epigenetic modifications, lactylation can modify histone proteins to alter the spatial configuration of chromatin, affect DNA accessibility and regulate the expression of corresponding genes. What's more, the degree of lactylation is inseparable from the spatialized lactate concentration, which builds a bridge between epigenetics and metabolic reprogramming. Here, we review the important role of lactate in energy reprogramming, summarize the latest finding of lactylation in tumorigenesis and try to explore therapeutic strategies in oncotherapy that can kill two birds with one stone.

Evolutionary dynamics of glucose-deprived cancer cells: insights from experimentally informed mathematical modelling

“…On the one hand, lactate may function as a signalling molecule, triggering regulatory pathways that promote the expression of MCT1 [7,15], thus mediating environment-induced changes in MCT1 expression [16]. On the other hand, lactate accumulation is known to cause reshaping of the tumour microenvironment and induce epigenetic changes in cancer cells [17].…”

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

“…[7][8][9] The alterations, which have the ability to be passed down and undone, have a significant impact on the specific control of cellular characteristics. 10,11 As a result, a variety of chromatin modifications, including methylation, acetylation, phosphorylation, ubiquitination, glycosylation and glutarylation, collectively contribute to distinct configurations that impact the efficacy of transcriptional machinery. [12][13][14] Significantly, the disturbance of epigenetic alterations and metabolic pathways is frequently linked to various illnesses, and the interaction between metabolism and chromatin presents numerous prospects for therapeutic interventions.…”

“…Multiple studies conducted over several decades have consistently demonstrated that changes in patterns of gene expression are primarily attributed to the process of chromatin remodelling and posttranslational modifications (PTMs), commonly referred to as epigenetic alterations 7–9 . The alterations, which have the ability to be passed down and undone, have a significant impact on the specific control of cellular characteristics 10,11 . As a result, a variety of chromatin modifications, including methylation, acetylation, phosphorylation, ubiquitination, glycosylation and glutarylation, collectively contribute to distinct configurations that impact the efficacy of transcriptional machinery 12–14 .…”

Lactylome analyses suggest systematic lysine- lactylated substrates in oral squamous cell carcinoma under normoxia and hypoxia

“…Recent studies have con rmed the regulatory roles of histone lactylation in in ammation, somatic cell reprogramming as well as oncogenesis [18][19][20]. Glis1 has been proved to induce epigenetic remodeling and pluripotency in somatic cells through the coordination of histone acetylation and lactylation [21].…”