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

A review of lactate-lactylation in malignancy: its potential in immunotherapy DOI Creative Commons

Jinhui Zha,

Juanjin Zhang,

Jingfen Lu

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 8, 2024

Lactic acid was formerly regarded as a byproduct of metabolism. However, extensive investigations into the intricacies cancer development have revealed its significant contributions to tumor growth, migration, and invasion. Post-translational modifications involving lactate been widely observed in histone non-histone proteins, these play crucial role regulating gene expression by covalently attaching lactoyl groups lysine residues proteins. This discovery has greatly enhanced our comprehension lactic acid's involvement disease pathogenesis. In this article, we provide comprehensive review intricate relationship between immunity, occurrence lactylation malignant tumors, exploitation targeted lactate-lactylation immunotherapy. Additionally, discuss future research directions, aiming offer novel insights that could inform investigation, diagnosis, treatment related diseases.

Language: Английский

Citations

16
Regulation of newly identified lysine lactylation in cancer DOI
Xin Gao,

Chaoyu Pang,

Zhiyao Fan

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 587, P. 216680 - 216680

Published: Feb. 10, 2024

Language: Английский

Citations

15
Comprehensive review of histone lactylation: Structure, function, and therapeutic targets DOI

Kaiwen Xu,

Zhang Keyi,

Yanshuang Wang

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 225, P. 116331 - 116331

Published: May 29, 2024

Language: Английский

Citations

14
LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma DOI Creative Commons
Mingdi Liu,

Liting Gu,

Yuning Zhang

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 595, P. 217025 - 217025

Published: June 5, 2024

Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim this research was to clarify and mechanism restraining telomerase activity adenocarcinoma. results showed that induced apoptosis either vitro or vivo. Overexpression LKB1-deficient A549 cells led inhibition induction telomere dysfunction by regulating reverse transcriptase (TERT) expression terms transcription. As a transcription factor, Sp1 mediated TERT after overexpression. lactate production inhibited histone H4 (Lys8) (Lys16) lactylation, which further altered Sp1-related transcriptional activity. inhibitor BIBR1532 beneficial for achieving optimum curative traditional chemotherapeutic drugs accompanied glycolysis 2DG. These data reveal new regulates through lactylation-dependent inhibition, therefore, provide insights into effects LKB1-mediated Our has opened up possibilities creation treatments.

Language: Английский

Citations

13
Constructing lactylation-related genes prognostic model to effectively predict the disease-free survival and treatment responsiveness in prostate cancer based on machine learning DOI Creative Commons

Jinyou Pan,

Jianpeng Zhang, Jingwei Lin

et al.

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: March 19, 2024

Background: Prostate cancer (PCa) is one of the most common malignancies in men with a poor prognosis. It therefore great clinical importance to find reliable prognostic indicators for PCa. Many studies have revealed pivotal role protein lactylation tumor development and progression. This research aims analyze effect lactylation-related genes on PCa Methods: By downloading mRNA-Seq data TCGA PCa, we obtained differential related Five machine learning algorithms were used screen key then five overlapping construct survival model by lasso cox regression analysis. Furthermore, relationships between pathways, mutation immune cell subpopulations, drug sensitivity explored. Moreover, two risk groups established according score calculated (LRGs). Subsequently, nomogram scoring system was predict disease-free (DFS) patients combining clinicopathological features scores. In addition, mRNA expression levels verified lines qPCR. Results: We identified 5 LRGs (ALDOA, DDX39A, H2AX, KIF2C, RACGAP1) constructed model. The AUC values 1 -, 3 5-year DFS dataset 0.762, 0.745, 0.709, respectively. found better predictor than traditional A that combined variables accurately predicted outcome patients. high-risk group higher proportion regulatory T cells M2 macrophage, burden, worse prognosis those low-risk group. had lower IC50 certain chemotherapeutic drugs, such as Docetaxel, Paclitaxel be highly expressed castration-resistant cells. Conclusion: can effectively therapeutic responses

Language: Английский

Citations

12
CAF-secreted LOX promotes PD-L1 expression via histone Lactylation and regulates tumor EMT through TGFβ/IGF1 signaling in gastric Cancer DOI
Zedong Li,

Panping Liang,

Zhengwen Chen

et al.

Cellular Signalling, Journal Year: 2024, Volume and Issue: 124, P. 111462 - 111462

Published: Oct. 10, 2024

Language: Английский

Citations

9
Lactate-induced protein lactylation in cancer: functions, biomarkers and immunotherapy strategies DOI Creative Commons
Wenjuan Wang, Hong Wang, Qi Wang

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 10, 2025

Lactate, long viewed as a byproduct of glycolysis and metabolic waste. Initially identified within the context yogurt fermentation, lactate's role extends beyond culinary applications to its significance in biochemical processes. Contemporary research reveals that lactate functions not merely terminal product but also nexus for initiating physiological pathological responses body. Lysine lactylation (Kla), novel post-translational modification (PTM) proteins, has emerged pivotal mechanism by which exerts regulatory influence. This epigenetic potential alter gene expression patterns, thereby impacting Increasing evidence indicates correlation between adverse prognosis various malignancies. Consequently, this review article aims encapsulate proteins interact with lactate, elucidate tumorigenesis progression, explore therapeutic targets afforded modulation lactylation. The objective is clarify oncogenic provide strategic framework future directions burgeoning field.

Language: Английский

Citations

1
Hypoxia‐Inducible Factor‐1α Regulates BNIP3‐Dependent Mitophagy and Mediates Metabolic Reprogramming Through Histone Lysine Lactylation Modification to Affect Glioma Proliferation and Invasion DOI Open Access
Feng Dong,

Haichang Yin,

Zhixing Zheng

et al.

Journal of Biochemical and Molecular Toxicology, Journal Year: 2025, Volume and Issue: 39(2)

Published: Jan. 20, 2025

ABSTRACT Objective Gliomas are the predominant form of malignant brain tumors. We investigated mechanism hypoxia‐inducible factor‐1α (HIF‐1α) affecting glioma metabolic reprogramming, proliferation and invasion. Methods Human cell U87 was cultured under hypoxia treated with small interfering (si)HIF‐1α, si‐B lymphoma‐2/adenovirus E1B 19‐kDa interacting protein 3 (siBNIP3), si‐YT521‐B homology domain 2 (siYTHDF2), 3‐methyladenine 2‐deoxyglucose, exogenous sodium lactate‐treated normally‐cultured cells as a lactate‐positive control. Cellular hexokinase 2, lactate dehydrogenase A pyruvate kinase 1 enzyme activities, glucose uptake, levels lactic acid adenosine triphosphate (ATP), HIF‐1α, glycolysis‐related proteins, mitophagy‐related histone H3 lysine 18 lactylation (H3K18la) YTHDF2 were determined by ELISA, 2‐NBDG, kits, Western blot. Extracellular acidification rate (ECAR), proliferation, invasion, apoptosis mitophagy evaluated extracellular flux analysis, CCK‐8, Transwell, flow cytometry, immunofluorescence staining. H3K18la‐YTHDF2 relationship YTHDF2‐BNIP3 interaction assessed ChIP Co‐IP assays. Results Hypoxia‐induced highly‐expressed HIF‐1α in increased levels, glycolytic production, ATP level ECAR, thereby promoting invasion proliferation. mediated through BNIP3‐dependent mitophagy, which partly negated inhibition. induced Kla modification to upregulate YTHDF2. downregulation impeded inhibited HIF‐1α‐induced curbing Conclusions high expression upregulated hH3K18la modification, enhanced interaction, regulated mitophagy‐mediated reprogramming affect

Language: Английский

Citations

1
Lactylation in cancer: metabolic mechanism and therapeutic strategies DOI Creative Commons
Ying Sui, Ziyang Shen, Zhenling Wang

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 20, 2025

Recent progress in cancer metabolism research has identified lactylation as a critical post-translational modification influencing tumor development and progression. The process relies on lactate accumulation the activation of lactate-sensitive acyltransferases. Beyond its role epigenetic regulation, emerged significant factor evolution, offering fresh opportunities for developing targeted therapies that transcend traditional approaches. This review explores growing importance biology highlights potential advancing diagnostic tools therapeutic strategies.

Language: Английский

Citations

1
Lactylation‐Driven HECTD2 Limits the Response of Hepatocellular Carcinoma to Lenvatinib DOI Creative Commons
Runyu Dong, Yao Fei,

Yi‐Ren He

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract Drug resistance remains a major hurdle for the therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). However, underlying mechanisms remain largely undetermined. Unbiased proteomic screening is performed to identify potential regulators HCC. Patient‐derived organoids, patient‐derived xenograft mouse models, and DEN/CCl 4 induced HCC models are constructed evaluate effects HECTD2 both vitro vivo. found be highly expressed lenvatinib‐resistant cell lines, patient tissues, organoids xenografts. In vivo experiments demonstrated that overexpression limits response treatment. Mechanistically, functions as an E3 ubiquitin ligase KEAP1, which contributes degradation KEAP1 protein. Subsequently, KEAP1/NRF2 signaling pathway initiates antioxidative cells. Lactylation histone 3 on lysine residue 18 facilitates transcription HECTD2. Notably, PLGA‐PEG nanoparticle‐based drug delivery system synthesized, effectively targeting The NPs achieved tumor‐targeting, controlled‐release, biocompatibility, making them promising strategy mitigating resistance. This study identifies nanotherapeutic target overcoming resistance, providing theoretical basis translational application

Language: Английский

Citations

1