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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(8): 973-976, 2024 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-39097282

RESUMO

OBJECTIVE: To explore the clinical characteristics and variant of CREBBP gene in a fetus with Rubinstein-Taybi syndrome (RSTS). METHODS: A fetus with RSTS diagnosed at the Third Affiliated Hospital of Zhengzhou University in August 2022 was selected as the study subject. Clinical data, amniotic fluid sample of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: Foot malformation, cerebellar vermis agenesis, brain agenesis, polysyndactyly of the big toes and other phenotypes were found by prenatal ultrasound. WES revealed that the fetus has harbored a heterozygous c.4684G>T (p.E1562*) variant in exon 28 of the CREBBP gene (NM_004380.3), which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PVS1+PS2_Moderate+PM2_Supporting). After genetic counseling, the couple had opted to terminate the pregnancy and refused autopsy of the fetus. CONCLUSION: The c.4684G>T (p.E1562*) variant of the CREBBP gene probably underlay the RSTS in this fetus. The newly discovered variant has enriched the mutational spectrum of the CREBBP gene and illustrated that WES is an efficient tool for the prenatal diagnosis of RSTS.


Assuntos
Proteína de Ligação a CREB , Sequenciamento do Exoma , Diagnóstico Pré-Natal , Síndrome de Rubinstein-Taybi , Humanos , Síndrome de Rubinstein-Taybi/genética , Feminino , Gravidez , Proteína de Ligação a CREB/genética , Adulto , Feto/anormalidades , Feto/diagnóstico por imagem , Mutação , Masculino , Ultrassonografia Pré-Natal
2.
J Chem Inf Model ; 64(12): 4739-4758, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38863138

RESUMO

Despite recent success in the computational approaches of cyclic peptide design, current studies face challenges in modeling noncanonical amino acids and nonstandard cyclizations due to limited data. To address this challenge, we developed an integrated framework for the tailored design of stapled peptides (SPs) targeting the bromodomain of CREBBP (CREBBP-BrD). We introduce a powerful combination of anchored stapling and hierarchical molecular dynamics to design and optimize SPs by employing the MultiScale integrative conformational dynamics assessment (MSICDA) strategy, which involves an initial virtual screening of over 1.5 million SPs, followed by comprehensive simulations amounting to 154.54 µs across 5418 of instances. The MSICDA method provides a detailed and holistic stability view of peptide-protein interactions, systematically isolated optimized peptides and identified two leading candidates, DA#430 and DA#99409, characterized by their enhanced stability, optimized binding, and high affinity toward the CREBBP-BrD. In cell-free assays, DA#430 and DA#99409 exhibited 2- to 12-fold greater potency than inhibitor SGC-CBP30. Cell studies revealed higher peptide selectivity for cancerous versus normal cells over small molecules. DA#430 combined with (+)-JQ-1 showed promising synergistic effects. Our approach enables the identification of peptides with optimized binding, high affinity, and enhanced stability, leading to more precise and effective cyclic peptide design, thereby establishing MSICDA as a generalizable and transformative tool for uncovering novel targeted drug development in various therapeutic areas.


Assuntos
Proteína de Ligação a CREB , Simulação de Dinâmica Molecular , Proteína de Ligação a CREB/química , Proteína de Ligação a CREB/metabolismo , Proteína de Ligação a CREB/antagonistas & inibidores , Humanos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/metabolismo , Domínios Proteicos , Conformação Proteica , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacologia , Linhagem Celular Tumoral , Ligação Proteica
3.
Medicina (Kaunas) ; 60(6)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38929606

RESUMO

Background and Objectives: This study aimed to investigate the relationship between neuropathic pain and CREB-binding protein (CBP) and methyl-CpG-binding protein 2 (MeCP2) expression levels in a rat model with spared nerve injury (SNI). Materials and Methods: Rat (male Sprague-Dawley white rats) models with surgical SNI (n = 6) were prepared, and naive rats (n = 5) were used as controls. The expression levels of CBP and MeCP2 in the spinal cord and dorsal root ganglion (DRG) were compared through immunohistochemistry at 7 and 14 days after surgery. The relationship between neuropathic pain and CBP/MeCP2 was also analyzed through intrathecal siRNA administration. Results: SNI induced a significant increase in the number of CBPs in L4 compared with contralateral DRG as well as with naive rats. The number of MeCP2 cells in the dorsal horn on the ipsilateral side decreased significantly compared with the contralateral dorsal horn and the control group. SNI induced a significant decrease in the number of MeCP2 neurons in the L4 ipsilateral DRG compared with the contralateral DRG and naive rats. The intrathecal injection of CBP siRNA significantly inhibited mechanical allodynia induced by SNI compared with non-targeting siRNA treatment. MeCP2 siRNA injection showed no significant effect on mechanical allodynia. Conclusions: The results suggest that CBP and MeCP2 may play an important role in the generation of neuropathic pain following peripheral nerve injury.


Assuntos
Proteína de Ligação a CREB , Modelos Animais de Doenças , Proteína 2 de Ligação a Metil-CpG , Neuralgia , Ratos Sprague-Dawley , Animais , Proteína 2 de Ligação a Metil-CpG/metabolismo , Proteína 2 de Ligação a Metil-CpG/genética , Neuralgia/metabolismo , Neuralgia/etiologia , Masculino , Ratos , Proteína de Ligação a CREB/metabolismo , Gânglios Espinais/metabolismo , RNA Interferente Pequeno , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/metabolismo , Medula Espinal/metabolismo , Imuno-Histoquímica
4.
J Med Chem ; 67(11): 9194-9213, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38829718

RESUMO

The epigenetic target CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) and its homologue p300 were promising therapeutic targets for the treatment of acute myeloid leukemia (AML). Herein, we report the design, synthesis, and evaluation of a class of CBP/p300 PROTAC degraders based on our previously reported highly potent and selective CBP/p300 inhibitor 5. Among the compounds synthesized, 11c (XYD129) demonstrated high potency and formed a ternary complex between CBP/p300 and CRBN (AlphaScreen). The compound effectively degraded CBP/p300 proteins and exhibited greater inhibition of growth in acute leukemia cell lines compared to its parent compound 5. Furthermore, 11c demonstrated significant inhibition of tumor growth in a MOLM-16 xenograft model (TGI = 60%) at tolerated dose schedules. Our findings suggest that 11c is a promising lead compound for the treatment of AML.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Camundongos , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína p300 Associada a E1A/metabolismo , Relação Estrutura-Atividade , Descoberta de Drogas , Proteína de Ligação a CREB/antagonistas & inibidores , Proteína de Ligação a CREB/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Fatores de Transcrição de p300-CBP/metabolismo , Proteólise/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos
5.
Genes (Basel) ; 15(6)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38927590

RESUMO

Rubinstein-Taybi syndrome (RTS) is a rare genetic disorder characterized by intellectual disability, facial dysmorphisms, and enlarged thumbs and halluces. Approximately 55% of RTS cases result from pathogenic variants in the CREBBP gene, with an additional 8% linked to the EP300 gene. Given the close relationship between these two genes and their involvement in epigenomic modulation, RTS is grouped into chromatinopathies. The extensive clinical heterogeneity observed in RTS, coupled with the growing number of disorders involving the epigenetic machinery, poses a challenge to a phenotype-based diagnostic approach for these conditions. Here, we describe the first case of a patient clinically diagnosed with RTS with a CREBBP truncating variant in mosaic form. We also review previously described cases of mosaicism in CREBBP and apply clinical diagnostic guidelines to these patients, confirming the good specificity of the consensus. Nonetheless, these reports raise questions about the potential underdiagnosis of milder cases of RTS. The application of a targeted phenotype-based approach, coupled with high-depth NGS, may enhance the diagnostic yield of whole-exome sequencing (WES) in mild and mosaic conditions.


Assuntos
Proteína de Ligação a CREB , Mosaicismo , Mutação , Fenótipo , Síndrome de Rubinstein-Taybi , Feminino , Humanos , Masculino , Proteína de Ligação a CREB/genética , Sequenciamento do Exoma/métodos , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/patologia
6.
J Appl Physiol (1985) ; 136(6): 1559-1567, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38722753

RESUMO

Mice with skeletal muscle-specific and inducible double knockout of the lysine acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP-response element-binding protein binding protein), referred to as i-mPCKO, demonstrate a dramatic loss of contractile function in skeletal muscle and ultimately die within 7 days. Given that many proteins involved in ATP generation and cross-bridge cycling are acetylated, we investigated whether these processes are dysregulated in skeletal muscle from i-mPCKO mice and, thus, whether they could underlie the rapid loss of muscle contractile function. Just 4-5 days after inducing knockout of p300 and CBP in skeletal muscle from adult i-mPCKO mice, there was ∼90% reduction in ex vivo contractile function in the extensor digitorum longus (EDL) and a ∼65% reduction in in vivo ankle dorsiflexion torque, as compared with wild type (WT; i.e., Cre negative) littermates. Despite this profound loss of contractile force in i-mPCKO mice, there were no genotype-driven differences in fatigability during repeated contractions, nor were there genotype differences in mitochondrial-specific pathway enrichment of the proteome, intermyofibrillar mitochondrial volume, or mitochondrial respiratory function. As it relates to cross-bridge cycling, remarkably, the overt loss of contractile function in i-mPCKO muscle was reversed in permeabilized fibers supplied with exogenous Ca2+ and ATP, with active tension being similar between i-mPCKO and WT mice, regardless of Ca2+ concentration. Actin-myosin motility was also similar in skeletal muscle from i-mPCKO and WT mice. In conclusion, neither mitochondrial abundance/function, nor actomyosin cross-bridge cycling, are the underlying driver of contractile dysfunction in i-mPCKO mice.NEW & NOTEWORTHY The mechanism underlying dramatic loss of muscle contractile function with inducible deletion of both E1A binding protein p300 (p300) and cAMP-response element-binding protein binding protein (CBP) in skeletal muscle remains unknown. Here, we find that impairments in mitochondrial function or cross-bridge cycling are not the underlying mechanism of action. Future work will investigate other aspects of excitation-contraction coupling, such as Ca2+ handling and membrane excitability, as contractile function could be rescued by permeabilizing skeletal muscle, which provides exogenous Ca2+ and bypasses membrane depolarization.


Assuntos
Camundongos Knockout , Contração Muscular , Músculo Esquelético , Animais , Contração Muscular/fisiologia , Músculo Esquelético/fisiologia , Músculo Esquelético/metabolismo , Camundongos , Processamento de Proteína Pós-Traducional , Proteína p300 Associada a E1A/metabolismo , Proteína de Ligação a CREB/metabolismo , Masculino , Cálcio/metabolismo , Trifosfato de Adenosina/metabolismo , Acetilação
7.
Biochem Biophys Res Commun ; 717: 150061, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38718570

RESUMO

Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR.


Assuntos
Apigenina , Transição Epitelial-Mesenquimal , Glucose , Histonas , Epitélio Pigmentado da Retina , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Animais , Apigenina/farmacologia , Acetilação/efeitos dos fármacos , Humanos , Glucose/metabolismo , Glucose/toxicidade , Histonas/metabolismo , Linhagem Celular , Camundongos , Fatores de Transcrição de p300-CBP/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Retinopatia Diabética/tratamento farmacológico , Proteína p300 Associada a E1A/metabolismo , Masculino , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proteína de Ligação a CREB/metabolismo , Proteína de Ligação a CREB/genética
8.
Stem Cell Res ; 78: 103456, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38820863

RESUMO

Rubinstein Taybi Syndrome (RSTS) is a rare genetic disorder which is caused by mutations in either CREBBP or EP300. RSTS with mutations in CREBBP is known as RSTS-1. We have generated an induced pluripotent stem cell (iPSC) line, IGIBi018-A from an Indian RSTS-patient using the episomal reprogramming method. The CREBBP gene in the patient harbours a nonsense mutation at position NM_004380.3(c.6876 del C). IGIBi018-A iPSC showed expression of pluripotent stem cell markers, has a normal karyotype and could be differentiated into three germ layers. This iPSC line will help to explore the role of CREBBP in RSTS associated developmental defects.


Assuntos
Células-Tronco Pluripotentes Induzidas , Síndrome de Rubinstein-Taybi , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/metabolismo , Síndrome de Rubinstein-Taybi/patologia , Linhagem Celular , Diferenciação Celular , Índia , Masculino , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo
9.
Endocrinology ; 165(6)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38717933

RESUMO

CYP19A1 encodes aromatase, which converts testosterone to estrogen, and is induced during placental maturation. To elucidate the molecular mechanism underlying this function, histone methylation was analyzed using the placental cytotrophoblast cell line, JEG3. Treatment of JEG3 cells with 3-deazaneplanocin A, an inhibitor of several methyltransferases, resulted in increased CYP19A1 expression, accompanied by removal of the repressive mark H3K27me3 from the CYP19A1 promoter. However, this increase was not observed in cells treated with GSK126, another specific inhibitor for H3K27me3 methylation. Expression of TFAP2C, which encodes AP-2γ, a transcription factor that regulates CYP19A1, was also elevated on 3-deazaneplanocin A treatment. Interestingly, TFAP2C messenger RNA (mRNA) was readily degraded in JEG3 cells but protected from degradation in the presence of 3-deazaneplanocin A. TFAP2C mRNA contained N6-methyladenosines, which were reduced on drug treatment. These observations indicate that the TFAP2C mRNA undergoes adenosine methylation and rapid degradation, whereas 3-deazaneplanocin A suppresses methylation, resulting in an increase in AP-2γ levels. We conclude that the increase in AP-2γ expression via stabilization of the TFAP2C mRNA is likely to underlie the increased CYP19A1 expression.


Assuntos
Aromatase , Regulação da Expressão Gênica , Placenta , Estabilidade de RNA , Fator de Transcrição AP-2 , Regiões Promotoras Genéticas , Aromatase/genética , Humanos , Linhagem Celular , Placenta/citologia , Placenta/metabolismo , Proteína de Ligação a CREB/metabolismo , Cromatina , Fator de Transcrição AP-2/metabolismo , Adenosina/análogos & derivados , Adenosina/uso terapêutico
10.
Oncogene ; 43(28): 2172-2183, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38783101

RESUMO

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.


Assuntos
Aurora Quinase A , Proteína de Ligação a CREB , Proteínas Proto-Oncogênicas c-myc , Mutações Sintéticas Letais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Aurora Quinase A/antagonistas & inibidores , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Apoptose/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cell Mol Life Sci ; 81(1): 160, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564048

RESUMO

The androgen receptor (AR) is a primary target for treating prostate cancer (PCa), forming the bedrock of its clinical management. Despite their efficacy, resistance often hampers AR-targeted therapies, necessitating new strategies against therapy-resistant PCa. These resistances involve various mechanisms, including AR splice variant overexpression and altered activities of transcription factors like the glucocorticoid receptor (GR) and FOXA1. These factors rely on common coregulators, such as EP300/CREBBP, suggesting a rationale for coregulator-targeted therapies. Our study explores EP300/CREBBP acetyltransferase inhibition's impact on steroid receptor and FOXA1 signaling in PCa cells using genome-wide techniques. Results reveal that EP300/CREBBP inhibition significantly disrupts the AR-regulated transcriptome and receptor chromatin binding by reducing the AR-gene expression. Similarly, GR's regulated transcriptome and receptor binding were hindered, not linked to reduced GR expression but to diminished FOXA1 chromatin binding, restricting GR signaling. Overall, our findings highlight how EP300/CREBBP inhibition distinctively curtails oncogenic transcription factors' signaling, suggesting the potential of coregulatory-targeted therapies in PCa.


Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/genética , Receptores de Glucocorticoides/genética , Fatores de Transcrição , Cromatina , Acetiltransferases , Fator 3-alfa Nuclear de Hepatócito/genética , Proteína p300 Associada a E1A/genética , Proteína de Ligação a CREB/genética
12.
Funct Integr Genomics ; 24(2): 75, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38600341

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally. Many herbal medicines and their bioactive compounds have shown anti-tumor properties. This study was conducted to examine the effect of psilostachyin C (PSC), a sesquiterpenoid lactone isolated from Artemisia vulgaris L., in the malignant properties of HCC cells. CCK-8, flow cytometry, wound healing, and Transwell assays revealed that 25 µM PSC treatment significantly suppressed proliferation, cell cycle progression, migration, and invasion of two HCC cell lines (Hep 3B and Huh7) while promoting cell apoptosis. Bioinformatics prediction suggests CREB binding protein (CREBBP) as a promising target of PSC. CREBBP activated transcription of GATA zinc finger domain containing 2B (GATAD2B) by binding to its promoter. CREBBP and GATAD2B were highly expressed in clinical HCC tissues and the acquired HCC cell lines, but their expression was reduced by PSC. Either upregulation of CREBBP or GATAD2B restored the malignant properties of HCC cells blocked by PSC. Collectively, this evidence demonstrates that PSC pocessess anti-tumor functions in HCC cells by blocking CREBBP-mediated transcription of GATAD2B.


Assuntos
Carcinoma Hepatocelular , Compostos Heterocíclicos com 3 Anéis , Neoplasias Hepáticas , Pironas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica
13.
Acta Neuropathol Commun ; 12(1): 60, 2024 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637838

RESUMO

Methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" was recently defined based on methylation profiling and tSNE analysis of a series of 21 neuroepithelial tumors with predominant presence of a BCOR fusion and/or characteristic CNV breakpoints at chromosome 22q12.31 and chromosome Xp11.4. Clear diagnostic criteria are still missing for this tumor type, specially that BCOR/BCOR(L1)-fusion is not a consistent finding in these tumors despite being frequent and that none of the Heidelberger classifier versions is able to clearly identify these cases, in particular tumors with alternative fusions other than those involving BCOR, BCORL1, EP300 and CREBBP. In this study, we introduce a BCOR::CREBBP fusion in an adult patient with a right temporomediobasal tumor, for the first time in association with methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" in addition to 35 cases of CNS neuroepithelial tumors with molecular and histopathological characteristics compatible with "CNS tumor with BCOR/BCOR(L1)-fusion" based on a comprehensive literature review and data mining in the repository of 23 published studies on neuroepithelial brain Tumors including 7207 samples of 6761 patients. Based on our index case and the 35 cases found in the literature, we suggest the archetypical histological and molecular features of "CNS tumor with BCOR/BCOR(L1)-fusion". We also present four adult diffuse glioma cases including GBM, IDH-Wildtype and Astrocytoma, IDH-Mutant with CREBBP fusions and describe the necessity of complementary molecular analysis in "CNS tumor with BCOR/BCOR(L1)-alterations for securing a final diagnosis.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Neoplasias Neuroepiteliomatosas , Adulto , Humanos , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/genética , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/genética , Metilação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteína de Ligação a CREB/genética
14.
Oncogene ; 43(25): 1900-1916, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38671157

RESUMO

The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Dano ao DNA , Histona-Lisina N-Metiltransferase , Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Transdução de Sinais , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Dano ao DNA/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Transdução de Sinais/genética , Animais , Camundongos , Linhagem Celular Tumoral , Metiltransferases/metabolismo , Metiltransferases/genética , Proteína de Ligação a CREB/metabolismo , Proteína de Ligação a CREB/genética , Rearranjo Gênico , Histonas/metabolismo , Histonas/genética , Fosforilação , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Acetilação
15.
J Med Chem ; 67(9): 6952-6986, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38649304

RESUMO

The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds 14g (XYD190) and 14h (XYD198) potently inhibited the growth of AML cells with low nanomolar IC50 values and effectively degraded CBP and p300 proteins in a concentration- and time-dependent manner. Mechanistic studies confirmed that 14g and 14h can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN- and proteasome-dependent manner. 14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.


Assuntos
Antineoplásicos , Proteólise , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Animais , Camundongos , Proteólise/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína p300 Associada a E1A/metabolismo , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína de Ligação a CREB/metabolismo , Proteína de Ligação a CREB/antagonistas & inibidores , Descoberta de Drogas , Ensaios Antitumorais Modelo de Xenoenxerto , Relação Estrutura-Atividade , Fatores de Transcrição de p300-CBP/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos Nus
16.
J Pathol ; 263(2): 242-256, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38578195

RESUMO

There are diverse phenotypes of castration-resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. In this study, we showed that BRD4, CBP, and p300 were co-expressed in AR-positive and AR-null prostate cancer. A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composition. NEO2734 treatment caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced ASCL1 levels and other neuroendocrine markers, and reduced tumour growth in vivo. Collectively, these results show that epigenome-targeted inhibitors cause decreased growth and phenotype-dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the clinic. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Proteína p300 Associada a E1A , Receptores Androgênicos , Transdução de Sinais , Masculino , Humanos , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Animais , Proteína p300 Associada a E1A/metabolismo , Proteína p300 Associada a E1A/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Regulação Neoplásica da Expressão Gênica , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas que Contêm Bromodomínio , Proteína de Ligação a CREB
18.
Zhonghua Er Ke Za Zhi ; 62(4): 351-356, 2024 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-38527506

RESUMO

Objective: To investigate the phenotypes of Rubinstein-Taybi syndrome (RSTS) caused by variants in the CREBBP or EP300 gene, and the correlation between genotype and phenotype. Methods: This case series study was performed on pediatric patients who were referred to the Children's Hospital of Capital Institute of Pediatrics between January 2013 and July 2022. Both point variant and copy number deletion in CREBBP or EP300 gene were detected by whole exome sequencing, chromosomal microarray analysis, or copy number variation sequencing (CNV-seq). The variant categories were summarized and phenotype numbers were re-visited for RSTS patients. Based on variant types, the patients were divided into different groups (point variant or copy number deletion, EP300 or CREBBP point variant, and loss of function or missense variant). Phenotype counts between different groups were compared using the rank-sum test of two independent samples. Results: A total of 21 RSTS patients were recruited, including 12 males and 9 females, with ages ranging from 1 month to 14 years and 2 months. Among them, 67% (14/21) had point variants, and 33% (7/21) had copy number deletions. Out of these, 20 variants (95%) were de novo. Among 20 patients finishing phenotype count during re-visit, 95% (19/20) of the patients exhibited developmental delays before the age of 2 years. Additionally, 80% (16/20) of the patients had distinctive facial features. Considering phenotype count, no statistically significant difference was found between point variant (14 cases) and copy number deletion (6 cases) (5.0 (3.0, 7.0) vs. 5.0 (2.5, 5.3), Z=0.75, P=0.452), CREBBP (10 cases) and EP300 gene (4 cases) point variant (5.0 (3.8, 7.0) vs. 4.0 (2.0, 6.0), Z=1.14, P=0.253), and loss of function (9 cases) and missense (5 cases) variant (6.0 (4.5, 7.0) vs. 3.0 (2.5, 5.5), Z=1.54, P=0.121). Conclusions: Patients with RSTS primarily exhibit developmental delays in early childhood. Specific facial features serve as suggested signs of genetic testing. However, no significant genotype-phenotype correlation is found.


Assuntos
Síndrome de Rubinstein-Taybi , Masculino , Feminino , Criança , Humanos , Pré-Escolar , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Variações do Número de Cópias de DNA , Genótipo , Fenótipo , Testes Genéticos , Proteína de Ligação a CREB/genética , Mutação
19.
J Med Chem ; 67(7): 5272-5274, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38517344

RESUMO

Transcriptional coactivators CBP/p300 have emerged as potential targets for cancer therapeutics. This Viewpoint discusses recent results that demonstrate an exceptionally potent and orally efficacious CBP/p300 degrader for the treatment of prostate cancer. This degrader stands out as a promising new candidate for cancer therapy and deserves further research.


Assuntos
Proteína de Ligação a CREB , Neoplasias da Próstata , Masculino , Humanos , Fatores de Transcrição , Neoplasias da Próstata/tratamento farmacológico
20.
HGG Adv ; 5(3): 100287, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-38553851

RESUMO

CREB-binding protein (CBP, encoded by CREBBP) and its paralog E1A-associated protein (p300, encoded by EP300) are involved in histone acetylation and transcriptional regulation. Variants that produce a null allele or disrupt the catalytic domain of either protein cause Rubinstein-Taybi syndrome (RSTS), while pathogenic missense and in-frame indel variants in parts of exons 30 and 31 cause phenotypes recently described as Menke-Hennekam syndrome (MKHK). To distinguish MKHK subtypes and define their characteristics, molecular and extended clinical data on 82 individuals (54 unpublished) with variants affecting CBP (n = 71) or p300 (n = 11) (NP_004371.2 residues 1,705-1,875 and NP_001420.2 residues 1,668-1,833, respectively) were summarized. Additionally, genome-wide DNA methylation profiles were assessed in DNA extracted from whole peripheral blood from 54 individuals. Most variants clustered closely around the zinc-binding residues of two zinc-finger domains (ZZ and TAZ2) and within the first α helix of the fourth intrinsically disordered linker (ID4) of CBP/p300. Domain-specific methylation profiles were discerned for the ZZ domain in CBP/p300 (found in nine out of 10 tested individuals) and TAZ2 domain in CBP (in 14 out of 20), while a domain-specific diagnostic episignature was refined for the ID4 domain in CBP/p300 (in 21 out of 21). Phenotypes including intellectual disability of varying degree and distinct physical features were defined for each of the regions. These findings demonstrate existence of at least three MKHK subtypes, which are domain specific (MKHK-ZZ, MKHK-TAZ2, and MKHK-ID4) rather than gene specific (CREBBP/EP300). DNA methylation episignatures enable stratification of molecular pathophysiologic entities within a gene or across a family of paralogous genes.


Assuntos
Proteína de Ligação a CREB , Metilação de DNA , Proteína p300 Associada a E1A , Humanos , Metilação de DNA/genética , Proteína de Ligação a CREB/genética , Masculino , Proteína p300 Associada a E1A/genética , Feminino , Criança , Adolescente , Pré-Escolar , Adulto , Fenótipo , Adulto Jovem , Síndrome de Rubinstein-Taybi/genética , Mutação , Domínios Proteicos/genética
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