New insights into the roles of lactylation in cancer

Abstract

Lactylation, a novel discovered posttranslational modification, is a vital component of lactate function and is prevalent in a wide range of cells, interacting with both histone and non-histone proteins. Recent studies have confirmed that lactylation as a new contributor to epigenetic landscape is involved in multiple pathological processes. Accumulating evidence reveals that lactylation exists in different pathophysiological states and leads to inflammation and cancer; however, few mechanisms of lactylation have been elaborated. This review summarizes the biological processes and pathophysiological roles of lactylation in cancer, as well as discusses the relevant mechanisms and potential therapeutic targets, aiming to provide new insights for targeted cancer therapy.

Keywords: cancer; histone and non-histone proteins; lactate; lactylation; therapeutic targets.

FIGURE 1

The biological process of lactylation. In the cytoplasm, glucose is transported into cells and is converted to pyruvate and methylglyoxal. On the one hand, pyruvate is converted into L-lactyl-CoA, which then acts as a direct substrate for K (L-la), transferring lactyl groups to lysine residues on histones through histone acetyltransferases such as p300. On the other hand, methylglyoxal is converted to lactoylglutathione, which then generates D (L-la) via nonenzymatic mechanism. Additionally, pyruvate can directly produce acetate through two distinct pathways: keto acid dehydrogenases and ROS-mediated pyruvate decarboxylation. Furthermore, acetate can be converted to acetyl-CoA through ACSS2.

FIGURE 2

The role of histone lactylation in cancer. H3K18la upregulates the expression of YTHDF, which promoting the degradation of PER1 and TP53, leading to the tumorigenesis; Downregulated CircXRN2 activates the Hippo signaling pathway and promotes tumor progression by inhibiting H3K18 lactylation; Lipopolysaccharide induces lactylation of LINC00152 and promotes the metastasis of tumor; Inactive von Hippel-Lindau promotes cancer progression by activating PDGFRβ through histone lactylation; GPR37 upregulates the expression of LDHA via Hippo signaling pathway, resulting in increasing H3K18la levels in tumors and promoting the metastasis of cancer cells.

FIGURE 3

The role of non-histone lactylation in cancer. The lactylation of K28 accelerates the proliferation and metastasis of HCC cells by inhibiting the function of AK2. CENPA is lactylated at the lysine 124, promoting its activation and facilitating tumor progression; SIRT3 can deacetylate non-histone proteins and prevent the occurrence of tumor; the lactylation of the non-histone protein PFKP at K688 directly attenuates it enzyme activity and promotes the progression of tumor.

FIGURE 4

The relevant mechanisms of lactylation in the development of cancer by modulating TME. Lactate can also be transported into cells via MCT1 and is converted to lactoyl-CoA, (a) which stimulates the expression of METTL3 in TIMs via H3K18 Kla lactylation and ultimately promotes the immunosuppressive capacity of TIMs. (b) Lactate accumulation and Kla promotes the expression of VEGFA and KIAA1199 via HIF-1α lactylation, thus participating in tumorigenesis via angiogenesis pathways. (c) Lactylation of MOESIN protein upregulates TGF-β signaling in Treg cells, thereby promoting the proliferation of Treg cells and enhancing the tumorigenesis.