Lactate and lysine lactylation of histone regulate transcription in cancer

Abstract

Histone lysine modifications were well-established epigenetic markers, with many types identified and extensively studied. The discovery of histone lysine lactylation had revealed a new form of epigenetic modification. The intensification of this modification was associated with glycolysis and elevated intracellular lactate levels, both of which were closely linked to cellular metabolism. Histone lactylation plays a crucial role in multiple cellular homeostasis, including immune regulation and cancer progression, thereby significantly influencing cell fate. Lactylation can modify both histone and non-histone proteins. This paper provided a comprehensive review of the typical epigenetic effects and lactylation on classical transcription-related lysine sites and summarized the known enzymes involved in histone lactylation and delactylation. Additionally, some discoveries of histone lactylation in tumor biology were also discussed, and some prospects for this field were put forward.

Keywords: Cancer; Histone; Lactate; Lysine lactylation; Post-translational modification; Transcription.

Fig. 1

Diagram of the Cori Cycle. The Cori Cycle illustrated the metabolic transformation of lactic acid and glucose. During intense exercise, the rate of glycolysis significantly exceeded the rate of NAD + formation via the respiratory chain. During this process, pyruvate produced by glycolysis in muscles was converted into lactic acid by LDH5, regenerating NAD+ and allowing glycolysis to continue. In liver cells, lactic acid was converted back into glucose by LDH1 via the gluconeogenesis pathway, and then released into the bloodstream to meet the glucose demands of muscle and brain tissues, thus facilitating the regeneration of NAD+ and the interconversion of lactic acid and glucose. LDH: lactate dehydrogenase.

Fig. 2

The schematic diagram illustrating histone lysine lactylation and its associated effects. The fundamental unit of chromatin, the nucleosome, was composed of a central histone octamer (two each of histones H2A, H2B, H3, and H4) and 147 base pairs of DNA. The lactate group attached to the lysine on the histone tail via a lactate 'writer,' creating a histone lysine lactylation modification that 'readers' can recognize to perform specific functions, which can be reversed by a lactate 'eraser'. Histone lactylation modifications changed the spatial configuration of chromatin, influenced DNA accessibility, and regulated the expression of numerous genes. Based on existing studies, the functions of H3K18la included: accelerating the occurrence of ocular melanoma by promoting the expression of YTHDF2; H3K18la enrichment in the promoter region up-regulated c-Myc and promoted breast cancer; promoting the progression of bladder cancer by enhancing the expression of LCN2; Arg1 expression was induced to stimulate the anti-inflammatory function of macrophages in sepsis; mediating hepatic stellate cell activation and pulmonary fibrosis; promoting vascular calcification; promoting AD; regulating osteoblast differentiation by activation of JunB; promoting FMT and thus myopia; mediating ZGA; driving YBX1 and YY1 to promote cisplatin resistance in BCa; and mediating bevacizumab treatment resistance in patients with colorectal cancer. Studies on H3K9la included: the inhibition of H3K9la by METTL15 to establish a study model of mitochondrial metabolism and histone lactation; DML inhibited H3K9la and thus inhibited LCSC tumorigenesis; activating Neu2 to facilitate myoblast differentiation; and mediating the emergence of TMZ resistance in GBM cells. H4K5la induced PD-L1 transcriptional activation, promoting the progression of AML. METTL15 inhibited H4K12la in a manner similar to its inhibition of H3K9la. The positive feedback loop involving glycolysis, H4K12la, and PKM2 can exacerbate microglial dysfunction in patients with AD. YTHDF2: YTH domain-containing protein 2; c-Myc: c-Myelocytomatosis; LCN2: Neutrophil gelatinase-associated lipocalin; Arg1: Arginase-1; AD: Alzheimer's disease; JunB: Transcription factor JunB; FMT: Fibroblasts transdifferentiate into myofibroblasts; ZGA: Major zygotic genome activation; YBX1: Y-box-binding protein 1; YY1: Zinc finger transcription factor YY1; BCa: Carcinoma of bladder; METTL15: 12S rRNA N4-methylcytidine (m4C) methyltransferase; DML: Demethylzeylasteral; LCSC: Liver cancer stem cell; Neu2: Vasopressin-neurophysin 2-copeptin; GBM: Glioblastoma; TMZ: Temozolomide; PD-L1: Programmed cell death 1 ligand 1; AML: Acute myeloid leukemia; PKM2: Pyruvate kinase isozyme type M2.

Fig. 3

Classification map of HDACs and sirtuins. The 18 human HDAC enzymes were classified into the Zn²⁺-dependent arginase/deacetylase superfamily and the NAD⁺-dependent deoxyhypusine synthase-like NAD/FAD-binding domain superfamily based on their dependence on metal ions or substrates for their deacetylase function. These were further categorized into the histone deacetylase family and the Sir2 regulator family. Based on yeast protein analogues, HDACs were divided into four classes. Class I RPD3-like proteins, including HDAC1, HDAC2, HDAC3, and HDAC8, were characterized by universal expression and primarily nuclear localization. Class II HDA1 proteins, including HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10, exhibited tissue-specific expression patterns and were localized in both the nucleus and cytoplasm. This class of HDACs was further subdivided into two subcategories: IIa, including HDAC4, HDAC5, HDAC7, and HDAC9, and IIb, comprising HDAC6 and HDAC10. Class III sirtuin proteins included SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7. SIRT1 and SIRT2 were located in both the nucleus and cytoplasm, while SIRT3, SIRT4, and SIRT5 were found in mitochondria. SIRT6 and SIRT7 were predominantly localized in the nucleus. Class IV contained HDAC11, predominantly found in the nucleus and cytoplasm. Recent studies indicated that HDAC1-3 can remove H3K18la and H4K5la, while SIRT2 and SIRT3 may function as lysine de-lactylation enzymes in the cytoplasm and mitochondria, respectively, based on their subcellular localization.