Key Epigenetic Players in Etiology and Novel Combinatorial Therapies for Treatment of Hepatocellular Carcinoma DOI Creative Commons
José Ernesto Belizário, Miguel Garay-Malpartida

Livers, Год журнала: 2024, Номер 4(4), С. 638 - 655

Опубликована: Ноя. 29, 2024

Hepatocellular carcinoma (HCC) is one of the leading causes death in which molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations oncogenes, DNA repair genes, tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory harmful epigenetic modifications chromatin—impacting expression involved proliferation, differentiation, genome stability, cell-cycle control, repair—are now acknowledged across various biological contexts contribute to etiology. Notably, dynamic hypermethylation hypomethylation enhancer promoter regions promote activation or silencing master regulatory programs often altered tumor cells due mutation. Genome instability hallmarks transdifferentiation intratumoral heterogeneity. Thus, it broadly accepted tissue dominated by genetically epigenetically distinct sub-clones display set mutations. Here we summarize some functions key players biochemical pathways liver cell transformation. We discuss role potential marks target thought be sequential events following lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, finally hepatocellular carcinoma. also briefly describe new findings showing how drugs together with chemotherapy immunotherapy improve overall responses patients hepatic tumors.

Язык: Английский

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight DOI Creative Commons
Anqi Li, Rui Wang, Yu-Qiang Zhao

и другие.

Metabolites, Год журнала: 2024, Номер 14(6), С. 325 - 325

Опубликована: Июнь 8, 2024

Epigenetic and metabolic reprogramming alterations are two important features of tumors, their reversible, spatial, temporal regulation is a distinctive hallmark carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, new entry point for tumor therapy. Moreover, drives hepatocellular carcinoma (HCC) initiation progression, highlighting significance metabolism in this disease. Exploring inter-regulatory relationship between epigenetic modification has become one hot directions current research. As viral etiologies have given way to dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it urgent that complex molecular pathways linking them hepatocarcinogenesis be explored. However, how aberrant crosstalk modifications affects MASLD-induced HCC lacks comprehensive understanding. A better understanding linkages necessary improve treatment strategies. For reason, review examines interwoven landscape carcinogenesis context focusing regulating development interactions while also updating advances modification-based therapeutic drugs HCC.

Язык: Английский

Процитировано

4
The epigenetic basis of hepatocellular carcinoma – mechanisms and potential directions for biomarkers and therapeutics DOI Creative Commons
Hong‐Yi Lin, Ah‐Jung Jeon, Kaina Chen

и другие.

British Journal of Cancer, Год журнала: 2025, Номер unknown

Опубликована: Март 8, 2025

Abstract Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis often late as current screening methods have limited sensitivity for early HCC. Moreover, treatment regimens intermediate-to-advanced HCC high resistance rates, no robust predictive biomarkers, survival benefits. A deeper understanding of molecular biology may enhance tumor characterization targeting key carcinogenic signatures. The epigenetic landscape includes hallmarks 1) global DNA hypomethylation oncogenes hypermethylation suppressors; 2) histone modifications, altering chromatin accessibility upregulate oncogene expression, and/or suppress suppressor gene expression; 3) genome-wide rearrangement loops facilitating distal enhancer-promoter oncogenic interactions; 4) RNA regulation via translational repression by microRNAs (miRNAs) modifications. Additionally, it useful consider etiology-specific aberrancies, especially in viral hepatitis metabolic dysfunction-associated steatotic liver disease (MASLD), which are main risk factors This article comprehensively explores signatures HCC, highlighting their potential biomarkers therapeutic targets. we examine how patterns integration therapies immunotherapy could advance personalized strategies.

Язык: Английский

Процитировано

0
Metabolic dysfunction-associated fatty liver disease/metabolic dysfunction-associated steatotic liver disease: general provisions DOI Creative Commons
А.Е. Абатуров, Anna Nikulina

CHILD`S HEALTH, Год журнала: 2024, Номер 19(2), С. 107 - 116

Опубликована: Апрель 24, 2024

The literature review deals with the problem of metabolic dysfunction-associated fatty liver disease that is poorly studied in pediatric gastroenterology. Until recently, primary hepatic steatosis not associated alcohol intake was defined as non-alcoholic disease. Given unity pathogenetic mechanisms underlying steatosis, steatohepatitis, fibrosis disorders, such visceral obesity, insulin resistance, meta-inflammation adipose tissue, it proposed to change terminology. authors present data on modern nomenclature definitions, etiological factors, prevalence, criteria disorders and this nosology specific childhood. Metabolic nonalcoholic are characterized by development hepatosteatosis. However, a distinguishing feature presence patient. It believed use term “metabolic disease” clinical practice allows doctors make diagnosis more reliably accurately modify patient’s lifestyle. Much attention paid description heterogeneity practice, concise list therapeutic options for childhood presented.

Язык: Английский

Процитировано

2
Post-translational histone modifications associated with the development of metabolic dysfunction-associated fatty liver disease. Part 1. General provisions DOI Creative Commons
А.Е. Абатуров, Anna Nikulina

GASTROENTEROLOGY, Год журнала: 2024, Номер 58(3), С. 210 - 221

Опубликована: Сен. 13, 2024

Based on the analysis of literary sources PubMed, MedLine, The Cochrane Library, EMBASE database, authors article give general provisions regarding post-translational modifications histones (small proteins with a molecular weight 10–15 kDa, which make up largest part nuclear proteins), are associated development metabolic dysfunction-associated fatty liver disease. emphasize that histone regulate activity gene expression, and each these types differently changes structure chromatin and, as result, expression. Currently, more than 20 protein have been identified (acetylation, biotinylation, butyrylation, 2-hydroxybutyrylation, ADP-ribosylation, N-formylation, hydroxylation, glycosylation, glutarylation, dopaminylation, proline isomerization aspartic acid carbonylation, crotonylation, lactylation, malonylation, methylation, propionylation, succinylation, SUMOylation, ubiquitination, phosphorylation, citrullination). Epigenetic epitranscriptomic induced by lifestyle, especially nature diet physical activity, influence exogenous endogenous factors. Prolonged epigenetic determine expression target genes can be accompanied disorders progression Histone modification is carried out site-specific enzymes: writers, identify marker, erasers, “erase” marker. Post-translational change local physicochemical environment based this, directly affect nucleosome chromatin. Also, N- C-terminal tails act “docking sites” recruit specific readers. Readers both in intranucleosomal space, modifying adjacent sites or recruiting transcription factors, activators repressors, internucleosomal space. also describe pathophysiological significance disease, diagnostic value biomarkers, potential pharmacological management to achieve inhibition pathological process.

Язык: Английский

Процитировано

2
Strategies to enhance the response of liver cancer to pharmacological treatments DOI
José J.G. Marı́n, Rocı́o I.R. Macı́as, Maitane Asensio

и другие.

AJP Cell Physiology, Год журнала: 2024, Номер 327(1), С. C11 - C33

Опубликована: Май 6, 2024

In contrast to other types of cancers, there is no available efficient pharmacological treatment improve the outcomes patients suffering from major primary liver i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation partly due existence in these tumors many different synergistic mechanisms resistance, accounting for lack response patients, not only classical chemotherapy but also more modern agents based on inhibition tyrosine kinase receptors (TKIs) stimulation immune against tumor using checkpoint inhibitors (ICIs). review summarizes efforts develop strategies overcome this severe limitation, including searching novel drugs derived synthetic, semisynthetic, or natural products with vectorial properties therapeutic targets increase drug uptake reduce export cancer cells. Besides, immunotherapy a promising line research that already starting be implemented clinical practice. Although less successful than foreseen future strategy treating cancers considerable. Similarly, epigenetic highly promising. Many “epidrugs,” able act “writer,” “reader,” “eraser” players, are currently being evaluated preclinical studies. Finally, gene therapy broad field fight chemoresistance, impressive advances recently achieved manipulation. sum, although present still dismal, reason hope non-too-distant future.

Язык: Английский

Процитировано

1
Targeting BRD4 mitigates hepatocellular lipotoxicity by suppressing the NLRP3 inflammasome activation and GSDMD-mediated hepatocyte pyroptosis DOI Creative Commons
Fangyuan Chen, Shuyu Li, Min Liu

и другие.

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Июль 9, 2024

Nod-like receptor family pyrin-containing protein 3 (NLRP3) inflammasome plays a pathologic role in metabolic dysfunction-associated steatohepatitis (MASH), but the molecular mechanism regulating NLRP3 activation hepatocellular lipotoxicity remains largely unknown. Bromodomain-containing 4 (BRD4) has emerged as key epigenetic reader of acetylated lysine residues enhancer regions that control transcription genes. The aim this study is to investigate if and how BRD4 regulated pyroptosis MASH. Using AML12 primary mouse hepatocytes stimulated by palmitic acid (PA) an vitro model lipotoxicity, we found targeting genetic knockdown or selective inhibitor MS417 protected against hepatosteatosis; protective effect was attributed inhibiting reducing expression Caspase-1, gasdermin D (GSDMD), interleukin (IL)-1β IL-6. Moreover, inhibition limited voltage-dependent anion channel-1 (VDAC1) oligomerization PA-treated hepatocytes, thereby suppressing activation. Additionally, enhanced MASH livers humans. Mechanistically, upregulated during turn modulated active mark H3K27ac at promoter Vdac Gsdmd genes, enhancing VDAC GSDMD. Altogether, our data provide novel insights into mechanisms underlying activating promoting GSDMD-mediated lipotoxicity. Thus, might serve therapeutic target for treatment

Язык: Английский

Процитировано

1
Frontiers in fatty liver: recent advances in pathogenic mechanisms, assessment of patients’ prognosis and pharmacotherapy DOI Open Access
Maite G. Fernández‐Barrena, Matías A. Ávila

Journal of Physiology and Biochemistry, Год журнала: 2023, Номер 79(4), С. 811 - 813

Опубликована: Окт. 21, 2023

Язык: Английский

Процитировано

3
Chronic Aroclor 1260 Exposure Alters the Mouse Liver Proteome, Selenoproteins, and Metals in Steatotic Liver Disease DOI
Kellianne M. Piell, Belinda J. Petri,

Jason Xu

и другие.

Environmental Toxicology and Pharmacology, Год журнала: 2024, Номер 107, С. 104430 - 104430

Опубликована: Март 27, 2024

Язык: Английский

Процитировано

0
Metabolic Dysfunction-Associated Steatotic Liver Disease Is Accompanied by Increased Activities of Superoxide Dismutase, Catalase, and Carbonyl Reductase 1 and Levels of miR-200b-3p in Mouse Models DOI Creative Commons
Gabriela Svobodová, Michaela Šadibolová,

Eva Velecká

и другие.

Antioxidants, Год журнала: 2024, Номер 13(11), С. 1371 - 1371

Опубликована: Ноя. 9, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes chronic disorders, is characterized by hepatic lipid accumulation. MASLD alterations in antioxidant defense system, lipid, and drug metabolism, resulting impaired status, metabolic processes, clearance therapeutic drugs, respectively. In pathogenesis, dysregulated epigenetic mechanisms (e.g., histone modifications, DNA methylation, microRNAs) play a substantial role. this study, development was investigated mice fed high-fat, high-fructose, high-cholesterol (FFC) diet from 2 months age, treated neonatally with monosodium glutamate (MSG) on standard (STD), MSG an FFC at 7 age compared to control (C) STD. Changes histology, detoxification enzymes, regulation, genes involved metabolism were compared. The strong steatosis observed STD, C FFC, significant fibrosis latter one. Moreover, regulatory factors, expressions activities various enzymes (namely superoxide dismutase, catalase, carbonyl reductase 1) mice. miR-200b-3p, highly significantly upregulated both groups, could be considered as potential diagnostic marker MASLD. seem suitable model dysregulation.

Язык: Английский

Процитировано

0
Key Epigenetic Players in Etiology and Novel Combinatorial Therapies for Treatment of Hepatocellular Carcinoma DOI Creative Commons
José Ernesto Belizário, Miguel Garay-Malpartida

Livers, Год журнала: 2024, Номер 4(4), С. 638 - 655

Опубликована: Ноя. 29, 2024

Hepatocellular carcinoma (HCC) is one of the leading causes death in which molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations oncogenes, DNA repair genes, tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory harmful epigenetic modifications chromatin—impacting expression involved proliferation, differentiation, genome stability, cell-cycle control, repair—are now acknowledged across various biological contexts contribute to etiology. Notably, dynamic hypermethylation hypomethylation enhancer promoter regions promote activation or silencing master regulatory programs often altered tumor cells due mutation. Genome instability hallmarks transdifferentiation intratumoral heterogeneity. Thus, it broadly accepted tissue dominated by genetically epigenetically distinct sub-clones display set mutations. Here we summarize some functions key players biochemical pathways liver cell transformation. We discuss role potential marks target thought be sequential events following lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, finally hepatocellular carcinoma. also briefly describe new findings showing how drugs together with chemotherapy immunotherapy improve overall responses patients hepatic tumors.

Язык: Английский

Процитировано

0