Clinical and Translational Medicine, Год журнала: 2022, Номер 12(1)
Опубликована: Янв. 1, 2022
Язык: Английский
Cancer Discovery, Год журнала: 2024, Номер 14(10), С. 1783 - 1809
Опубликована: Окт. 4, 2024
Abstract Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, latest iteration of cancer hallmarks, “nonmutational epigenetic reprogramming” was newly added. However, epigenetics, much like genetics, broad scientific area that deserves further attention due its multiple roles initiation, progression, adaptive nature. Herein, we present detailed examination hallmarks affected human cancer, elucidating genes involved, dissecting disrupted landscapes for DNA methylation, histone modifications, chromatin architecture define disease. Significance: characterized by constant evolution, spanning from initial premalignant stages advanced invasive disseminated stages. It pathology able adapt survive amidst hostile microenvironments diverse treatments implemented medical professionals. The more fixed setup genetic structure cannot fully provide transformed cells with tools but rapid plastic nature changes ready task. This review summarizes ecological success our bodies.
Язык: Английский
Процитировано
23
Frontiers in Pharmacology, Год журнала: 2021, Номер 11
Опубликована: Янв. 26, 2021
Background: The upregulated expression of BET proteins is closely associated with the occurrence and development hematological malignancies solid tumors. Several inhibitors have been developed, some in phase I/II clinical trials. Here, safety, efficacy, pharmacodynamics ten currently trials were evaluated. Methods: We retrieved reviewed published reports on twelve including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, ODM-207 for patients tumors summarized their target genes. Results: In monotherapy inhibitors, most common severe (grade ≥3) adverse events (AEs) are thrombocytopenia, anemia, neutropenia. non-hematological syndromes diarrhea, nausea, fatigue, dysgeusia, decreased appetite, while AE pneumonia. Additionally, Tmax these was between 0.5-6 h, but range T1/2 varied significantly. According to data, rates SD, PD, CR PR 27.4%, 37.6%, 3.5%, 5.7%, respectively, which not very satisfactory. addition BRD4, oncogene MYC another gene inhibitors. Ninety-seven signaling pathways may be regulated by Conclusion: All our study exhibited exposure-dependent limit application. Moreover, further efforts necessary explore optimal dosing schemes combinations maximize efficacy
Язык: Английский
Процитировано
104
Medicinal Research Reviews, Год журнала: 2020, Номер 41(1), С. 223 - 245
Опубликована: Сен. 14, 2020
Abstract Clinical development of bromodomain and extra‐terminal (BET) protein inhibitors differs from the traditional course drug development. These drugs are simultaneously being evaluated for treating a wide spectrum human diseases due to their novel mechanism action. BET proteins epigenetic “readers,” which play primary role in transcription. Here, we briefly describe family proteins, BRD4 has been studied most extensively. We discuss activity at latent enhancers as an example function. examine redistribution enhancer reprogramming embryonic development, cancer, cardiovascular, autoimmune, metabolic diseases, presenting hallmark studies that highlight attractive targets therapeutic intervention. review currently available approaches targeting methods selectively individual bromodomains, compare effects selective inhibition those pan‐BET inhibition. Lastly, current clinical landscape inhibitor
Язык: Английский
Процитировано
91
Nature Communications, Год журнала: 2020, Номер 11(1)
Опубликована: Июль 7, 2020
Abstract The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but also lead to fibrosis and progressive disease. There is currently limited knowledge about transcriptional regulators regulating these programs. Herein we establish the enhancer super-enhancer landscape AKI by ChIP-seq uninjured repairing kidneys on day two ischemia reperfusion (IRI). We identify key transcription factors including HNF4A, GR, STAT3 STAT5, which show specific binding at sites, revealing dynamics changes during repair. Loss bromodomain-containing protein 4 function before IRI leads impaired increased mortality. Our comprehensive analysis epigenetic vivo has potential targets for therapeutic intervention. Importantly, our data call attention caveats involved use BET inhibitors patients risk AKI.
Язык: Английский
Процитировано
86
Frontiers in Molecular Biosciences, Год журнала: 2021, Номер 8
Опубликована: Сен. 3, 2021
The BET (bromodomain and extra-terminal domain) family proteins, consisting of BRD2, BRD3, BRD4, testis-specific BRDT, are widely acknowledged as major transcriptional regulators in biology. They characterized by two tandem bromodomains (BDs) that bind to lysine-acetylated histones transcription factors, recruit factors coactivators target gene sites, activate RNA polymerase II machinery for elongation. Pharmacological inhibition proteins with BD inhibitors has been shown a promising therapeutic strategy the treatment many human diseases including cancer inflammatory disorders. recent advances bromodomain protein biology have further uncovered complex versatile functions regulation expression chromatin. In this review article, we highlight our current understanding proteins’ mediating protein–protein interactions required chromatin-templated splicing, chromatin remodeling, DNA replication, damage repair. We discuss context-dependent activator vs. repressor individual isoforms, may be harnessed future development emerging epigenetic therapies
Язык: Английский
Процитировано
85
Nature Communications, Год журнала: 2021, Номер 12(1)
Опубликована: Июль 27, 2021
Abstract Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene Here, we explore the mechanistic role of super-enhancers linking TNFα amplification in AH. RNA-seq and histone modification ChIP-seq human explants show upregulation multiple CXCL chemokines Liver sinusoidal endothelial cells (LSEC) identified as an important source expression liver, regulated by TNFα/NF-κB signaling. A super-enhancer for genes approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition Bromodomain Extraterminal (BET) proteins, transcriptional regulators vital function, decreases vitro murine models Our findings highlight propagating inflammatory signaling inducing therapeutic potential BET AH treatment.
Язык: Английский
Процитировано
80
Journal of Medicinal Chemistry, Год журнала: 2020, Номер 63(17), С. 9045 - 9069
Опубликована: Июль 21, 2020
Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family proteins. They have shown profound efficacy in vitro vivo oncology immunomodulatory models, a number them are currently clinical trials where significant safety signals been reported. It is therefore important to understand functional contribution each bromodomain assess opportunity tease apart toxicity. This article discloses cellular activity profiles GSK789, potent, cell-permeable, highly selective inhibitor first family.
Язык: Английский
Процитировано
74
Nature Reviews Gastroenterology & Hepatology, Год журнала: 2021, Номер 18(9), С. 630 - 647
Опубликована: Май 11, 2021
Язык: Английский
Процитировано
74
Journal of Internal Medicine, Год журнала: 2021, Номер 291(1), С. 11 - 31
Опубликована: Сен. 26, 2021
Abstract Non‐alcoholic fatty liver disease is comprised of either simple steatosis (non‐alcoholic liver) or a more advanced inflammatory and fibrogenic stage steatohepatitis [NASH]). NASH affects growing proportion the global adult pediatric population, leading to rising rates fibrosis hepatocellular carcinoma. multifactorial that part systemic metabolic disorder. Here, we provide an overview underpinnings pathogenesis established drivers inflammation fibrosis. Clarification underlying mechanisms will advance development novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches potential investigational derived from animal models including inflammasome, epigenetic reprogramming, Hippo signaling, Notch engineered T cells remove HSCs, HSC‐specific targeting therapies. Recently completed ongoing clinical trials antifibrotics discussed, illuminating expectation one yield benefit in coming years.
Язык: Английский
Процитировано
74
Current Opinion in Chemical Biology, Год журнала: 2022, Номер 68, С. 102148 - 102148
Опубликована: Апрель 21, 2022
Язык: Английский
Процитировано
69