Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling

Li, Xiu-Ming; Yang, Yun; Jiang, Fu-Quan; Hu, Guang; Wan, Shan; Yan, Wen-Ying; He, Xiao-Shun; Xiao, Fei; Yang, Xue-Mei; Guo, Xin; Lu, Jun-Hou; Yang, Xiao-Qin; Chen, Jun-Jie; Ye, Wen-Long; Liu, Yue; He, Kuang; Duan, Han-Xiao; Zhou, Yu-Jia; Gan, Wen-Juan; Liu, Feng; Wu, Hua

doi:10.1016/j.celrep.2024.113688

Cited by 12 publications

(2 citation statements)

References 59 publications

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“…Moreover, HCC patients who showed responsiveness to anti-PD-1 therapy exhibited reduced levels of MOESIN Kla modification in their Treg cells relative to non-responding patients [ 76 ]. In CRC cells, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing IL-6 levels in the TME and endowing macrophages with tumor-promoting functions [ 77 ]. Notably, Zhu et al found that the pivotal function of Kla in modulating cellular plasticity and neuroendocrine differentiation within the context of prostate and lung adenocarcinomas.…”

Section: Protein Lactylation In Pathological Processesmentioning

confidence: 99%

Lactylation: the novel histone modification influence on gene expression, protein function, and disease

Hu,

He,

et al. 2024

Clin Epigenet

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Lactic acid, traditionally considered as a metabolic waste product arising from glycolysis, has undergone a resurgence in scientific interest since the discovery of the Warburg effect in tumor cells. Numerous studies have proved that lactic acid could promote angiogenesis and impair the function of immune cells within tumor microenvironments. Nevertheless, the precise molecular mechanisms governing these biological functions remain inadequately understood. Recently, lactic acid has been found to induce a posttranslational modification, lactylation, that may offer insight into lactic acid's non-metabolic functions. Notably, the posttranslational modification of proteins by lactylation has emerged as a crucial mechanism by which lactate regulates cellular processes. This article provides an overview of the discovery of lactate acidification, outlines the potential “writers” and “erasers” responsible for protein lactylation, presents an overview of protein lactylation patterns across different organisms, and discusses the diverse physiological roles of lactylation. Besides, the article highlights the latest research progress concerning the regulatory functions of protein lactylation in pathological processes and underscores its scientific significance for future investigations.

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Section: Protein Lactylation In Pathological Processesmentioning

confidence: 99%

Lactylation: the novel histone modification influence on gene expression, protein function, and disease

Hu,

He,

et al. 2024

Clin Epigenet

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“…Inactive von Hippel-Lindau (VHL) promotes the progression of clear cell renal cell carcinoma by initiating a positive feedback loop between histone lactylation and platelet-derived growth factor receptor β (PDGFRβ) signaling ( Yang J. et al, 2022 ). Recent studies have demonstrated that lactylation modification plays a significant role in promoting tumor progression in various types of cancer, including prostate cancer ( Luo et al, 2022 ), colorectal cancer ( Wang et al, 2022a ; Li X. M. et al, 2024 ), ocular melanoma ( Gu et al, 2024 ), gastric cancer ( Sun et al, 2023 ), bladder cancer ( Xie et al, 2023 ) and cervical cancer ( Meng et al, 2024 ). By binding to lactate, alanyl-tRNA synthetase 1 (AARS1) is able to catalyze the formation of lactate-AMP complex, thereby promoting p53 lactylation and tumor growth ( Zong et al, 2024 ).…”

Section: Function Of Protein Lactylationmentioning

confidence: 99%

Lactylation: The emerging frontier in post-translational modification

Lu,

Zheng,

Shi

et al. 2024

Front. Genet.

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Lactate, a metabolic byproduct, has gained recognition as a highly influential signaling molecule. Lactylation, an emerging form of post-translational modification derived from lactate, plays a crucial role in numerous cellular processes such as inflammation, embryonic development, tumor proliferation, and metabolism. However, the precise molecular mechanisms through which lactylation governs these biological functions in both physiological and pathological contexts remain elusive. Hence, it is imperative to provide a comprehensive overview of lactylation in order to elucidate its significance in biological processes and establish a foundation for forthcoming investigations. This review aims to succinctly outline the process of lactylation modification and the characterization of protein lactylation across diverse organisms. Additionally, A summary of the regulatory mechanisms of lactylation in cellular processes and specific diseases is presented. Finally, this review concludes by delineating existing research gaps in lactylation and proposing primary directions for future investigations.

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Lactylation in cancer: Mechanisms in tumour biology and therapeutic potentials

He,

Song,

Ning

et al. 2024

Clinical & Translational Med

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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.

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Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling

Cited by 12 publications

References 59 publications

Lactylation: the novel histone modification influence on gene expression, protein function, and disease

Lactylation: the novel histone modification influence on gene expression, protein function, and disease

Lactylation: The emerging frontier in post-translational modification

Lactylation in cancer: Mechanisms in tumour biology and therapeutic potentials

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