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Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Acetylation at lysine residues represents an abundant highlighted mark known to display its role in the regulatory mechanism of cellular processes like transcription. Acetylation at the histone residues of H/H4 is directly correlated with the expression of the gene. Bromodomain, structural motifs, act as epigenetic readers present in all different proteins that play a specific role in recognizing acetylated lysines and transcriptional regulation [41]. Despite direct effector recruitment, histone acetylation introduces certain changes in the structure of chromatin physically by neutralizing observable charge of lysines residues and disrupts the intra- and inter-nucleosomal interactions results in the open structure of chromatin, which provide the permissible environment for transcription. Acetylation of these three lysine residues on H3-based globular domains, H3K122, H3K64, and H3K56, is present on the H3–DNA interface that might disrupt nucleosomal interactions and also is directly linked with gene activation [43–45]. H3K122ac, lysine residue, has also shown its role to promote in vitro transcription by means of process stimulation of histone eviction [44]. Acetylation at the tail of H3 and H4 histone residues stimulates DNA unwrapping, whereas acetylation at H3 residues plays a role in nucleosome sensitization towards salt-induced dissociation [46]. H3/H4 and H3K4me3 acetylation generally coexist at TSS and promoter regions of specific active genes.
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
The bromodomain and extraterminal bromodomain (BET) protein inhibitor, JQ1, which inhibits BRD4 by competitive inhibition of the acetyl-lysine recognition motif, has been shown to reduce cell viability due to arrest at G1 phase followed by an increase in tumor cell apoptosis in an MYC-amplified MB model. JQ1 suppressed MYC expression and inhibited MYC-associated targets [85-87]. Similarly, other BRD4 inhibitors are under current investigation [88]. A cyclin-dependent kinase inhibitor, alsterpaullone (ALP), was shown recently to reduce cell proliferation in vitro and improve mortality in an in vivo mouse model of Group 3 MB via the downregulation of MYC expression [89]. Additionally, the folate synthesis inhibitor, pemetrexed, and the nucleoside analog, gemcitabine, demonstrated a synergistic effect in reducing neurosphere proliferation in vitro, inhibiting tumor cell proliferation in vivo, and increasing the survival of mice bearing MYC-overexpressing tumors [90, 91].
Rubinstein−Taybi Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CREBBP gene on chromosome 16p13.3 comprises 31 transcribed exons spanning 154 kb. The 3-prime distal flanking region of the CREBBP gene contains the DNASE1 and TRAP1 (or HSP75) genes. The CREBBP gene encodes a 2442 aa nuclear transcriptional coactivator protein (CREBBP) of 265 kDa, which includes a central region (consisting of a bromodomain and a histone acetyltransferase [HAT] domain) flanked by two transactivation domains. While the bromodomain facilitates protein−protein interactions, the HAT domain demonstrates intrinsic histone acetyltransferase activity, which plays a vital role in the regulation of gene expression through acetylation of histones H3 and H4, de-condensing chromatin and allowing for transcription. In addition, the transactivation domains recruit and interact with transcriptional machinery such as RNA polymerase II (Pol II) complex, co-activators, and repressors. Through these functionally distinct domains, CREBBP acts as a mediator of different signaling pathways, a negative regulator of the cell cycle by repressing the transition from G1 to S phase, and also a scaffold to stabilize additional protein interactions with the transcription complex via chromatin remodeling [1].
Mantle cell lymphoma: insights into therapeutic targets at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
The bromodomain (BRD) and extra-terminal (BET) family of proteins recruit transcriptional regulatory complexes to acetylated, transcriptionally permissive chromatin [100]. The C-terminal positive transcription elongation factor b (pTEFb), a heterodimer composed of cyclin T and CDK9, binds to BRD4 protein and regulates activity of RNA polymerase II. BRD4 thus couples histone acetylation to transcription. BET protein bromodomain antagonists (BA) demonstrated promising anti-tumor activity in a wide range of malignancies. Displacement of BRD4 and pTEFb from the acetylated chromatin decreases transcription of key oncogenes (e.g. MYC, CCND1, CDK4, and BCL2) and genes involved in BCR signaling (e.g. B-cell linker protein, PAX5, IKZF3) [101]. The inhibitors also block aberrant activation of NFkappaB and have shown promising anti-lymphoma activity in bortezomib or ibrutinib-resistant MCL [102–105].
Targeting epigenetic regulators in the treatment of T-cell lymphoma
Published in Expert Review of Hematology, 2020
Bromodomains represent a conserved family of motifs that recognize and bind acetylated lysine residues in histone tails, thereby facilitating recruitment of protein complexes that enable transcription [127]. BET bromodomains have two tandem N-terminal bromodomains and an extra-terminal domain at the C-terminus. BET bromodomains are critical in transcriptional elongation and are important in regulating expression of genes such as MYC, NF-B-dependent genes, and cell cycle genes that play a central role in various cancers including lymphoma [128]. Following initial development of the BET inhibitor JQ1 [129], at least 14 BET inhibitor compounds have been or are being tested in clinical trials for solid tumors and/or hematologic malignancies [127]. While these trials have not specifically targeted T-cell lymphoma and limited data are available on efficacy in lymphomas in general [130], preclinical studies have shown promising results alone or in combination in cutaneous T-cell lymphoma and some ALCLs [131–133].
A patent review of BRD4 inhibitors (2013-2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Tian Lu, Wenchao Lu, Cheng Luo
The bromodomain protein family has attracted great attention of major pharmaceutical companies and research institutions due to its potential therapeutic value in the treatment of cancers and inflammatory diseases. Garnier and Ghoshal et al. have explicitly reported these patents, highlighted the importance of bromodomain inhibitors in the treatment of human diseases especially their use in cancer therapy [35,40]. Herein, we give an updated review of the patents, relative pharmacological activities and corresponding indications of BRD4 small molecule inhibitors from 2013 to 2019. Figure 2 shows the number and trend of BRD4 small molecule inhibitor patents published annually since 2013, as well as the number of applications filed by some representative companies and academic institutions.