Beyond metabolic waste: lysine lactylation and its potential roles in cancer progression and cell fate determination

Wang, Jun-Han; Mao, Ling; Wang, Jun; Zhang, Xiao; Wu, Min; Wen, Qian; Yu, Shanshan

doi:10.1007/s13402-023-00775-z

Cited by 25 publications

(17 citation statements)

References 126 publications

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“…A good understanding of these processes can help provide important clues for disease diagnosis and treatment, such as in AD the interruption of the feedback loop can help the treatment of patients [ 98 ], whereas the Kla of the K673 site may be able to help cure nonalcoholic fatty liver disease [ 103 ]. Although the relationship between Kla and other PTMs has not been explored in depth, and has only been hypothesized as competitive, synergistic, and crosstalk [ 104 ], it can be affirmed that Kla is an essential balancing mechanism in diverse organisms. We hope our summary of Kla can contribute to a better understanding of this phenomenon and aid in the exploration of novel approaches for the intervention of complex diseases such as cancer.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitous protein lactylation in health and diseases

Wang,

Wang

et al. 2024

Cell Mol Biol Lett

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For decades, lactate has been considered a byproduct of glycolysis. The lactate shuttle hypothesis shifted the lactate paradigm, demonstrating that lactate not only plays important roles in cellular metabolism but also cellular communications, which can transcend compartment barriers and can occur within and among different cells, tissues and organs. Recently, the discovery that lactate can induce a novel post-translational modification, named lysine lactylation (Kla), brings forth a new avenue to study nonmetabolic functions for lactate, which has inspired a ‘gold rush’ of academic and commercial interest. Zhang et al. first showed that Kla is manifested in histones as epigenetic marks, and then mounting evidences demonstrated that Kla also occurs in diverse non-histone proteins. The widespread Kla faithfully orchestrates numerous biological processes, such as transcription, metabolism and inflammatory responses. Notably, dysregulation of Kla touches a myriad of pathological processes. In this review, we comprehensively reviewed and curated the existing literature to retrieve the new identified Kla sites on both histones and non-histone proteins and summarized recent major advances toward its regulatory mechanism. We also thoroughly investigated the function and underlying signaling pathway of Kla and comprehensively summarize how Kla regulates various biological processes in normal physiological states. In addition, we also further highlight the effects of Kla in the development of human diseases including inflammation response, tumorigenesis, cardiovascular and nervous system diseases and other complex diseases, which might potentially contribute to deeply understanding and interpreting the mechanism of its pathogenicity. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Ubiquitous protein lactylation in health and diseases

Wang,

Wang

et al. 2024

Cell Mol Biol Lett

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“…A crucial role of lactate accumulation in cancer cells has been demonstrated regarding its ability to induce expression of anti-inflammatory and proangiogenic genes, together with the modification of histones through a process called “lactylation”, where a lactyl-CoA is added to lysine residues present in the tails of histones [ 33 ]. This epigenetic alteration results in cancer progression, drug resistance [ 34 ], metastasis and stemness induction [ 35 , 36 ], metabolic alterations by affecting enzymes involved in the tricarboxylic acid cycle (TCA), and carbohydrate, amino acid, fatty acid, and nucleotide metabolism [ 35 ], hence opening the way to the generation of novel therapeutic strategies against lysine lactylation, not only regarding histones (Fig. 1 ) [ 36 ].…”

Section: Oncometabolites and Their Impact On The Epigenetic Landscape...mentioning

confidence: 99%

“…This epigenetic alteration results in cancer progression, drug resistance [ 34 ], metastasis and stemness induction [ 35 , 36 ], metabolic alterations by affecting enzymes involved in the tricarboxylic acid cycle (TCA), and carbohydrate, amino acid, fatty acid, and nucleotide metabolism [ 35 ], hence opening the way to the generation of novel therapeutic strategies against lysine lactylation, not only regarding histones (Fig. 1 ) [ 36 ]. Finally, it is worth noting that other metabolic intermadiates or biochemical molecules may accumulate in cancer cells [ 37 ], thus emerging as other possible oncometabolites, hence maintaing open the inclusion in this class of pro-cancer molecules.…”

Section: Oncometabolites and Their Impact On The Epigenetic Landscape...mentioning

confidence: 99%

Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies

Ambrosini,

Cordani,

Zarrabi

et al. 2024

Cell Commun Signal

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Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies. Graphical Abstract

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“…In conclusion, as a new type of PTM, our understanding of the lactylation modification sites, process and reaction kinetics is still limited ( 37 , 38 ). Protein acylation is an evolutionally-conserved and reversible PTM ( 39 ), and currently, based on the generality of lysine acylation and biochemical analysis of other acylation reactions ( 27 ), we have known that those involved in lactylation modification include specific lactylases (Writers), de-lactylases (Erasers), and lactylation recognition enzymes (Readers), which perform the functions of adding lactate CoA to or removing it from histones, and recognizing lactylation modifications, respectively. It has been reported that from a non-PTM perspective, p300 is a transcriptional co-activator that can activate oncogene transcription, promote tumor cell growth, regulate immune function, etc.…”

Section: Lactylation: the “New Favorite” In Epigenetic Modificationmentioning

confidence: 99%

“…The TME contains a variety of cell types, which can provide a great metabolic environment for lactylation ( 26 , 27 ). However, the interaction between metabolic reprogramming, histone lactylation and immunosuppression in the TME, including tumor cells, immune cells and stromal cells, is still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Histone lactylation regulates cancer progression by reshaping the tumor microenvironment

Qu,

Li,

Sun

2023

Front. Immunol.

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As a major product of glycolysis and a vital signaling molecule, many studies have reported the key role of lactate in tumor progression and cell fate determination. Lactylation is a newly discovered post-translational modification induced by lactate. On the one hand, lactylation introduced a new era of lactate metabolism in the tumor microenvironment (TME), and on the other hand, it provided a key breakthrough point for elucidation of the interaction between tumor metabolic reprogramming and epigenetic modification. Studies have shown that the lactylation of tumor cells, tumor stem cells and tumor-infiltrating immune cells in TME can participate in the development of cancer through downstream transcriptional regulation, and is a potential and promising tumor treatment target. This review summarized the discovery and effects of lactylation, as well as recent research on histone lactylation regulating cancer progression through reshaping TME. We also focused on new strategies to enhance anti-tumor effects via targeting lactylation. Finally, we discussed the limitations of existing studies and proposed new perspectives for future research in order to further explore lactylation targets. It may provide a new way and direction to improve tumor prognosis.

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Beyond metabolic waste: lysine lactylation and its potential roles in cancer progression and cell fate determination

Cited by 25 publications

References 126 publications

Ubiquitous protein lactylation in health and diseases

Ubiquitous protein lactylation in health and diseases

Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies

Histone lactylation regulates cancer progression by reshaping the tumor microenvironment

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