Histone lactylation enhances GCLC expression and thus promotes chemoresistance of colorectal cancer stem cells through inhibiting ferroptosis DOI Creative Commons
Jiao Deng, Yangkun Li, Lanlan Yin

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 20, 2025

Abstract Colorectal cancer stem cells (CCSCs) play a critical role in mediating chemoresistance. Lactylation is post-translational modification induced by lactate that regulates gene expression. However, whether lactylation affects the chemoresistance of CCSCs remains unknown. Here, we demonstrate histone enhances CCSC both vitro and vivo. Furthermore, our findings showed p300 catalyzes H4 at K12, whereas HDAC1 facilitates its delactylation CCSCs. Notably, H4K12 (H4K12la) upregulates GCLC expression inhibits ferroptosis CCSCs, inhibition or LDHA decreases H4K12la levels, thereby increasing chemosensitivity Additionally, inhibitor BSO promotes sensitizes to oxaliplatin. Taken together, these suggest inhibit signaling, thus enhancing These provide new insights into relationship between cellular metabolism potential therapeutic strategies targeting p300, LDHA, GCLC.

Language: Английский

Histone H3K9 Lactylation Confers Temozolomide Resistance in Glioblastoma via LUC7L2‐Mediated MLH1 Intron Retention DOI Creative Commons
Yue Qu,

Zhao Wang,

Yixiong Shen

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(19)

Published: March 13, 2024

Abstract Temozolomide (TMZ) resistance remains the major obstacle in treatment of glioblastoma (GBM). Lactylation is a novel post‐translational modification that involved various tumors. However, whether lactylation plays role GBM TMZ unclear. Here it found histone H3K9 (H3K9la) confers via LUC7L2‐mediated intron 7 retention MLH1. Mechanistically, upregulated recurrent tissues and TMZ‐resistant cells, mainly concentrated H3K9. Combined multi‐omics analysis, including CUT&Tag, SLAM‐seq, RNA‐seq, reveals significantly enriched LUC7L2 promoter activates transcription to promote its expression. mediates MLH1 reduce expression, thereby inhibit mismatch repair (MMR), ultimately leading resistance. Of note, identified clinical anti‐epileptic drug, stiripentol, which can cross blood–brain barrier lactate dehydrogenase A/B (LDHA/B) activity, acts as inhibitor renders cells more sensitive vitro vivo. These findings not only shed light on mechanism but also provide potential combined therapeutic strategy for treatment.

Language: Английский

Citations

41
H3K18 Lactylation Potentiates Immune Escape of Non-Small Cell Lung Cancer DOI
Zhang Cai, Lijie Zhou,

Mingyuan Zhang

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(21), P. 3589 - 3601

Published: Aug. 13, 2024

Abstract Recently discovered epigenetic modification lysine lactylation contributes to tumor development and progression in several types of cancer. In addition the tumor-intrinsic effects, histone may mediate microenvironment remodeling immune evasion. this study, we observed elevated pan–lysine H3 18 (H3K18la) levels non–small cell lung cancer (NSCLC) tissues, which was positively correlated with poor patient prognosis. Interruption glycolysis by 2-deoxy-D-glucose oxamate treatment silencing lactate dehydrogenase A B reduced H3K18la circumvented evasion NSCLC cells enhancing CD8+ T-cell cytotoxicity. Mechanistically, directly activated transcription pore membrane protein 121 (POM121), enhanced MYC nuclear transport direct binding CD274 promoter induce PD-L1 expression. a mouse xenograft model, combination therapy inhibitor an anti-PD-1 antibody induced intratumoral function exhibited strong antitumor efficacy. Overall, work revealed that potentiates escape activating POM121/MYC/PD-L1 pathway, offers insights into role posttranslational modifications carcinogenesis provides rationale for developing epigenetic-targeted strategy treating NSCLC. Significance: H3K18 supports immunosuppression non-small inducing POM121 increase activity expression, can be reversed metabolic reprogramming immunotherapy treatment.

Language: Английский

Citations

34
Histone lactylation: from tumor lactate metabolism to epigenetic regulation DOI Creative Commons

Xiaoning Yu,

Jing Yang,

Jin Xu

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(5), P. 1833 - 1854

Published: Jan. 1, 2024

The Warburg Effect is one of the most well-known cancer hallmarks.This metabolic pattern centered on lactate has extremely complex effects various aspects tumor microenvironment, including remodeling, immune suppression, cell migration, and drug resistance development.Based accumulating evidence, metabolites are likely to participate in regulation biological processes microenvironment form a feedback loop.Therefore, further revealing key mechanism lactate-mediated oncological reasonable scientific idea.The discovery refinement histone lactylation recent years laid firm foundation for above idea.Histone post-translational modification that occurs at lysine sites histones.Specific enzymes, known as "writers" "erasers", catalyze addition or removal, respectively, lactacyl group target sites.An increasing number investigations have reported this multiple cellular procedures.In review, we discuss close connection between series tumorigenesis, infiltration, energy metabolism.Finally, review provides insightful perspectives, identifying promising avenues exploration potential clinical application field research.

Language: Английский

Citations

28
Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases DOI Creative Commons

Weiyi Yao,

Xinting Hu,

Xin Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 16, 2024

Abstract Histone post-translational modifications (HPTMs), as one of the core mechanisms epigenetic regulation, are garnering increasing attention due to their close association with onset and progression diseases potential targeted therapeutic agents. Advances in high-throughput molecular tools abundance bioinformatics data have led discovery novel HPTMs which similarly affect gene expression, metabolism, chromatin structure. Furthermore, a growing body research has demonstrated that histone also play crucial roles development various diseases, including cancers, cardiovascular infectious psychiatric disorders, reproductive system diseases. This review defines nine modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, 2-hydroxybutyrylation. It comprehensively introduces modification processes these HPTMs, transcription, replication, DNA repair recombination, structure, well involvement promoting occurrence clinical applications targets biomarkers. Moreover, this provides detailed overview HPTM inhibitors targeting emerging strategies treatment multiple while offering insights into future prospects challenges. Additionally, we briefly introduce techniques field research.

Language: Английский

Citations

21
Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription DOI Creative Commons
Yu Zhang, Hang Song, Meili Li

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(3)

Published: March 1, 2024

Abstract Heightened lactate production in cancer cells has been linked to various cellular mechanisms such as angiogenesis, hypoxia, macrophage polarisation and T‐cell dysfunction. The lactate‐induced lactylation of histone lysine residues is noteworthy, it functions an epigenetic modification that directly augments gene transcription from chromatin. This originating effectively fosters a reliance on transcription, thereby expediting tumour progression development. Herein, this review explores the correlation between characteristics, revealing innovative process enhances vulnerability malignancy. Moreover, imperative acknowledge paramount importance acknowledging therapeutic methodologies for proficiently managing by precisely targeting signalling. comprehensive illuminates crucial yet inadequately investigated aspect lactylation, providing valuable insights into its clinical ramifications prospective interventions centred lactylation.

Language: Английский

Citations

19
Lactate and lactylation in cancer DOI Creative Commons
Jie Chen, Ziyue Huang,

Ya Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 11, 2025

Abstract Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation fate regulation in physiological pathological settings, particularly intricate conditions such as cancer. Specifically, been demonstrated to be pivotal molding tumor microenvironment (TME) through its effects different cell populations. Within cells, impacts signaling pathways, augments shuttle process, boosts resistance oxidative stress, contributes lactylation. In various populations, interplay between immune cells governs processes differentiation, response, surveillance, treatment effectiveness. Furthermore, communication stromal/endothelial supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, drug resistance. Focusing production transport, specifically dehydrogenase (LDH) monocarboxylate transporters (MCT), shown promise Inhibitors targeting LDH MCT act both suppressors enhancers immunotherapy, leading a synergistic therapeutic effect when combined with immunotherapy. The review underscores importance progression provides valuable perspectives potential approaches that target vulnerability metabolism, highlighting Heel Achilles for cancer treatment.

Language: Английский

Citations

12
Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN DOI Creative Commons
Yuan Zeng, Haoran Jiang, Zhoufeng Chen

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 31, 2025

Language: Английский

Citations

4
Histone lactylation-driven B7-H3 expression promotes tumor immune evasion DOI Creative Commons
Zhibo Ma,

Jianming Yang,

Wenlong Jia

et al.

Theranostics, Journal Year: 2025, Volume and Issue: 15(6), P. 2338 - 2359

Published: Jan. 13, 2025

Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous checkpoints, particularly those within B7 family. Elucidating mechanisms that govern induction family molecules is crucial for advancement immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, suggested may play role in reshaping tumor microenvironment and facilitating evasion. Methods: We analyzed glycolysis pathway's enrichment patients with immune-evading tumors assessed impact lactate treatment on antitumor immunity CD8+ T microenvironment. interrupted using dehydrogenase A (LDHA) knockdown sodium oxamate, evaluated its effects cell cytotoxicity. Additionally, we investigated correlation between B7-H3 expression pathway, explored molecular underlying lactate-induced expression. Results: Our findings revealed pathway was highly enriched tumors. Lactate inhibited cells, whereas interruption via LDHA or oxamate augmented cytotoxicity effectively counteracting found be closely linked pathway. Mechanistically, lactate-upregulated H3K18la directly bound promoter conjunction transcription factor Creb1 co-activator Ep300, leading increased contributing progression by compromising proportion tumor-infiltrating cells. In mouse bearing models, inhibiting suppressed growth, activated demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced efficacy anti-PD-1 treatment. Conclusions: This study uncovers novel mechanism which modulates through expression, providing new avenues metabolism-targeted

Language: Английский

Citations

3
Lactylation in health and disease: physiological or pathological? DOI Creative Commons
Lijun Zhao,

Haonan Qi,

Huiying Lv

et al.

Theranostics, Journal Year: 2025, Volume and Issue: 15(5), P. 1787 - 1821

Published: Jan. 2, 2025

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles different aspects of energy metabolism signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as novel posttranslational modification (PTM). Research indicates that Kla essential balancing mechanism variety organisms involved many biological processes pathways. closely related to disease development represents potential important new drug target. In line with existing reports, we searched for newly discovered sites on histone nonhistone proteins; reviewed the mechanisms (particularly focusing enzymes directly reversible regulation Kla, including "writers" (modifying enzymes), "readers" (modification-binding "erasers" (demodifying enzymes); summarized crosstalk between PTMs help researchers better understand widespread distribution diverse functions. Furthermore, considering "double-edged sword" role both pathological contexts, this review highlights "beneficial" states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) "detrimental" pathogenic or inducive effects processes, particularly malignant tumors complex nontumor diseases. We also clarify molecular health disease, discuss feasibility therapeutic Finally, describe detection technologies their applications diagnosis clinical settings, aiming provide insights treatment diseases accelerate translation from laboratory research practice.

Language: Английский

Citations

2
Non-histone lactylation: unveiling its functional significance DOI Creative Commons
Peng Shi, Yongjie Ma, Shangzhe Zhang

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 24, 2025

Lactylation, a newly discovered protein posttranslational modification (PTM) in 2019, primarily occurs on lysine residues. Lactylation of histones was initially identified, and subsequent studies have increasingly demonstrated its widespread presence non-histone proteins. Recently, high-throughput proteomics identified large number lactylated proteins sites, revealing their global regulatory role disease development. Notably, this is catalyzed by lactyltransferase reversed delactylase, with numerous new enzymes, such as AARS1/2, reported to be involved. Specifically, these revealed how lactylation exerts influence through alterations spatial conformation, molecular interactions, enzyme activity subcellular localization. Indeed, implicated various physiological pathological processes, including tumor development, cardiovascular cerebrovascular diseases, immune cell activation psychiatric disorders. This review provides the latest advancements research roles lactylation, highlighting crucial scientific importance for future studies.

Language: Английский

Citations

2