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Lactylation in cancer: Mechanisms in tumour biology and therapeutic potentials - PubMed

Review

Lactylation in cancer: Mechanisms in tumour biology and therapeutic potentials

Yipeng He et al. Clin Transl Med. 2024 Nov.

Abstract

Lactylation, a recently identified form of protein post-translational modification (PTM), has emerged as a key player in cancer biology. The Warburg effect, a hallmark of tumour metabolism, underscores the significance of lactylation in cancer progression. By regulating gene transcription and protein function, lactylation facilitates metabolic reprogramming, enabling tumours to adapt to nutrient limitations and sustain rapid growth. Over the past decade, extensive research has revealed the intricate regulatory network underlying lactylation in tumours. Large-scale sequencing and machine learning have confirmed the widespread occurrence of lactylation sites across the tumour proteome. Targeting lactylation enzymes or metabolic pathways has demonstrated promising anti-tumour effects, highlighting the therapeutic potential of this modification. This review comprehensively explores the mechanisms of lactylation in cancer cells and the tumour microenvironment. We expound on the application of advanced omics technologies for target identification and data modelling within the lactylation field. Additionally, we summarise existing anti-lactylation drugs and discuss their clinical implications. By providing a comprehensive overview of recent advancements, this review aims to stimulate innovative research and accelerate the translation of lactylation-based therapies into clinical practice. KEY POINTS: Lactylation significantly influences tumour metabolism and gene regulation, contributing to cancer progression. Advanced sequencing and machine learning reveal widespread lactylation sites in tumours. Targeting lactylation enzymes shows promise in enhancing anti-tumour drug efficacy and overcoming chemotherapy resistance. This review outlines the clinical implications and future research directions of lactylation in oncology.

Keywords: clinical translation; lactylation; post translational modification; tumour biology; tumour microenvironment.

© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

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Conflict of interest statement

The authors declare no competing interests.

Figures

FIGURE 1
FIGURE 1

Four mechanisms of lactylation modification. The process of lactylation modification can be divided into enzymatic and non‐enzymatic reactions. Enzymatic reactions are mediated by different enzymes and can occur in the nucleus, cytoplasm and mitochondrial matrix. Non‐enzymatic reactions can take place in the cytoplasm.

FIGURE 2
FIGURE 2

Pathways related to lactylation modifications in tumour cells. Extensive histone lactylation modifications within tumour cells drive the expression of various genes. The proteins corresponding to the expression of these genes activate downstream biological pathways in the cytoplasm, such as RNA alternative splicing and modification, as well as various classic signalling and metabolic pathways. Some of these proteins target glycolysis, leading to further increases in intracellular lactate levels, while others function as transcription factors that drive the expression of additional oncogenes. The metabolic network, derived from the core processes of glycolysis and lactylation modifications, elucidates the mechanisms underlying the malignant behaviour of tumour cells in a high‐lactate environment.

FIGURE 3
FIGURE 3

Relevant pathways of lactylation modifications in the tumour microenvironment. The increase in lactate within the TME leads to the lactylation of infiltrating cell proteins, ultimately assisting the tumour in adapting to and exploiting the microenvironment. Tumour cells upregulate glycolysis, exporting large amounts of lactate into the microenvironment. This elevated lactate level in infiltrating cells subsequently increases the lactylation levels of their intracellular proteins. Across various immune cell types, including macrophages, T cells, T‐reg cells, or tumour‐infiltrating myeloid (TIM) cells, the upregulation of intracellular lactylation is associated with a shift towards immunosuppressive and pro‐tumour phenotypes ultimately promoting tumour survival and proliferation.

FIGURE 4
FIGURE 4

Different drugs inhibiting the glycolysis‐lactylation pathway. Different substances inhibit the glycolysis‐lactylation pathway. 2‐DG inhibits hexokinase, thereby preventing the conversion of glucose to glucose‐6‐phosphate. CircXRN2 has been shown to inhibit the glycolysis pathway. Royal jelly acid inhibits LDH, thus preventing the conversion of pyruvate to lactate. C646 inhibits the histone lactylation writer enzyme p300. Honokiol promotes the activity of the histone modification eraser enzyme SIRT.

FIGURE 5
FIGURE 5

Four potential directions for clinical translation. Currently, there are four possible directions for the clinical translation of lactylation modification: personalised therapy, chemoresistance, anti‐angiogenic therapy and cancer stem cells. In personalised therapy, the addition of Wnt inhibitors to PI3Ki+MEKi therapy in non‐responsive mice has been shown to inhibit downstream lactylation modification, achieving a 100% response rate in these previously non‐responsive mice. Regarding chemoresistance, the upregulation of various signalling molecules activates the glycolysis‐lactylation axis. Both histone and non‐histone lactylation modifications downstream enhance tumour resistance to chemotherapy. In anti‐angiogenic therapy, the use of bevacizumab leads to increased tumour lactylation modification and elevated autophagy levels. For cancer stem cells, lactylation modifications induced by multiple signalling pathways contribute to enhanced tumour stemness.

FIGURE 6
FIGURE 6

Major development directions in the field of lactylation modifications.

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