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1.
J Clin Invest ; 134(6)2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38300709

RESUMEN

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.


Asunto(s)
Melanoma , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Co-Represoras/genética , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Fenotipo , Proteínas Quinasas p38 Activadas por Mitógenos
3.
Am J Dermatopathol ; 45(2): 147-148, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36669083
4.
Am J Dermatopathol ; 45(2): e7-e8, 2023 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-36669088
5.
Cureus ; 15(12): e51043, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38264371

RESUMEN

We present the case of a 68-year-old man with no known risk factors for HIV infection who developed a new, rapidly growing lesion on the left medial foot. The lesion was biopsied and found to be consistent with Kaposi sarcoma (KS). He subsequently tested positive for HIV and developed cellulitis of the left lower extremity. Treatment involved empiric antibiotics, surgical excision of the lesion, radiation therapy, and antiretroviral therapy. The development of KS with no known history of HIV/AIDS is uncommon, with only a few reported cases. We provide a summary of 18 cases in the current literature of cutaneous KS as an initial presenting sign of HIV/AIDS.

6.
Crit Rev Oncol Hematol ; 174: 103696, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35523374

RESUMEN

The scope of dermatologic adverse events to ibrutinib has not been systematically described. We sought to determine the incidence and severity of ibrutinib-associated dermatologic toxicities and provide management recommendations. We conducted a systematic literature search of clinical trials and cohorts investigating ibrutinib monotherapy for cancer or chronic graft-versus-host disease through June 2020. Thirty-two studies with 2258 patients were included. The incidence of all-grade toxicities included cutaneous bleeds (24.8%; 95%CI, 18.6-31.0%), mucocutaneous infections (4.9%; 95%CI, 2.9-7.0%), rash (10.8%; 95%CI. 6.1-15.5%), mucositis (6%; 95%CI, 3.6-8.5%), edema (15.9%; 95%CI, 11.1-20.6%), pruritus (4.0%; 95%CI, 0.0-7.9%), xerosis (9.2%; 95%CI, 5.5-13.0%), nail changes (17.8%; 95%CI, 4.1-31.5%), and hair changes (7.9%; 95%CI, 0.0-21.3%). The incidence of high-grade toxicities included mucocutaneous infection (1.3%; 95%CI, 0.5-2.2%), rash (0.1%; 95%CI, 0.0-0.2%), mucositis (0.1%; 95%CI, 0.0-0.3%), and edema (0.1%; 95%CI, 0.0-0.2%). It is imperative that clinicians familiarize themselves with ibrutinib-associated dermatologic toxicities to learn how to manage them, prevent discontinuation, and improve patient outcomes.


Asunto(s)
Exantema , Mucositis , Adenina/análogos & derivados , Humanos , Piperidinas
7.
JID Innov ; 2(2): 100090, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35199090

RESUMEN

This past decade has seen tremendous advances in understanding the molecular pathogenesis of melanoma and the development of novel effective therapies for melanoma. Targeted therapies and immunotherapies that extend survival of patients with advanced disease have been developed; however, the vast majority of patients experience relapse and therapeutic resistance over time. Moreover, cellular plasticity has been demonstrated to be a driver of therapeutic resistance mechanisms in melanoma and other cancers, largely functioning through epigenetic mechanisms, suggesting that targeting of the cancer epigenetic landscape may prove a worthwhile endeavor to ensure durable treatment responses and cures. Here, we review the epigenetic alterations that characterize melanoma development, progression, and resistance to targeted therapies as well as epigenetic therapies currently in use and under development for melanoma and other cancers. We further assess the landscape of epigenetic therapies in clinical trials for melanoma and provide a framework for future advances in epigenetic therapies to circumvent the development of therapeutic resistance in melanoma.

8.
J Womens Health (Larchmt) ; 30(6): 864-871, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-32407186

RESUMEN

Women currently represent nearly half of all medical school graduates and assistant professors at academic institutions. Despite the large pool of women in the academic medicine pipeline, relatively few ascend to top leadership positions and women remain grossly underrepresented among full professors, permanent department chairs, and highest-level deans/interim deans. Considerable evidence suggests that the gender imbalance observed at the top tiers of academic medicine is, in part, due to gender differences in promotional rates, with women being promoted more slowly than their male colleagues. The well-documented gender gaps in publications, grant support, recognition awards, speaker invitations, and leadership positions contribute to the slow progression of women in medicine, as promotions committees rely heavily upon these traditional measures of academic success to select candidates for career advancement. Additionally, implicit biases, which have been shown to favor men over women in science and leadership, influence decision-making processes relevant to the promotion of women in academia. With the large number of highly qualified women entering medicine, it is imperative that organizations, academic institutions, and leaders in the medical community address the systemic inequities that are preventing half the workforce from reaching its full potential.


Asunto(s)
Médicos Mujeres , Movilidad Laboral , Docentes Médicos , Femenino , Humanos , Liderazgo , Masculino , Facultades de Medicina
9.
Cancer Cell ; 36(5): 528-544.e10, 2019 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-31631026

RESUMEN

H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Glioma/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Histona Demetilasas/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/patología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular Tumoral , Cromatina/metabolismo , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Epigénesis Genética/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Glioma/genética , Glioma/mortalidad , Glioma/patología , Código de Histonas/efectos de los fármacos , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histonas/metabolismo , Humanos , Ratones , Mutación , Puente/patología , RNA-Seq , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Cancer Res ; 79(10): 2649-2661, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-30910803

RESUMEN

Histone modifications, largely regulated by histone acetyltransferases (HAT) and histone deacetylases, have been recognized as major regulatory mechanisms governing human diseases, including cancer. Despite significant effort and recent advances, the mechanism by which the HAT and transcriptional coactivator p300 mediates tumorigenesis remains unclear. Here, we use a genetic and chemical approach to identify the microphthalmia-associated transcription factor (MITF) as a critical downstream target of p300 driving human melanoma growth. Direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions was coupled to cellular proliferation, suggesting a significant growth regulatory axis. Further analysis revealed forkhead box M1 (FOXM1) as a key effector of the p300-MITF axis driving cell growth that is selectively activated in human melanomas. Targeted chemical inhibition of p300 acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. Collectively, these data confirm the critical role of the p300-MITF-FOXM1 axis in melanoma and support p300 as a promising novel epigenetic therapeutic target in human melanoma. SIGNIFICANCE: These results show that MITF is a major downstream target of p300 in human melanoma whose expression is predictive of melanoma response to small-molecule inhibition of p300 HAT activity.


Asunto(s)
Proteína p300 Asociada a E1A/genética , Melanoma/genética , Factor de Transcripción Asociado a Microftalmía/genética , Acetilación , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Senescencia Celular/genética , Proteína Forkhead Box M1/genética , Regulación Neoplásica de la Expresión Génica/genética , Histona Acetiltransferasas/genética , Humanos
11.
J Biol Chem ; 290(40): 24367-80, 2015 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-26294766

RESUMEN

The cardiomyocyte cell cycle is a poorly understood process. Mammalian cardiomyocytes permanently withdraw from the cell cycle shortly after birth but can re-enter the cell cycle and proliferate when subjected to injury within a brief temporal window in the neonatal period. Thus, investigating the mechanisms of cell cycle regulation in neonatal cardiomyocytes may provide critical insight into the molecular events that prevent adult myocytes from proliferating in response to injury or stress. MEF2D is a key transcriptional mediator of pathological remodeling in the adult heart downstream of various stress-promoting insults. However, the specific gene programs regulated by MEF2D in cardiomyocytes are unknown. By performing genome-wide transcriptome analysis using MEF2D-depleted neonatal cardiomyocytes, we found a significant impairment in the cell cycle, characterized by the up-regulation of numerous positive cell cycle regulators. Expression of Pten, the primary negative regulator of PI3K/Akt, was significantly reduced in MEF2D-deficient cardiomyocytes and found to be a direct target gene of MEF2D. Consistent with these findings mutant cardiomyocytes showed activation of the PI3K/Akt survival pathway. Paradoxically, prolonged deficiency of MEF2D in neonatal cardiomyocytes did not trigger proliferation but instead resulted in programmed cell death, which is likely mediated by the E2F transcription factor. These results demonstrate a critical role for MEF2D in cell cycle regulation of post-mitotic, neonatal cardiomyocytes in vitro.


Asunto(s)
Miocitos Cardíacos/citología , Animales , Animales Recién Nacidos , Apoptosis , Caspasa 3/metabolismo , Ciclo Celular , Proliferación Celular , Supervivencia Celular , Factores de Transcripción E2F/metabolismo , Fibroblastos/metabolismo , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/fisiología , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Transcriptoma
13.
PLoS One ; 10(5): e0127641, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26011708

RESUMEN

The myocyte enhancer factor 2 (MEF2) transcription factor requires interactions with co-factors for precise regulation of its target genes. Our lab previously reported that the mammalian MEF2A isoform regulates the cardiomyocyte costamere, a critical muscle-specific focal adhesion complex involved in contractility, through its transcriptional control of genes encoding proteins localized to this cytoskeletal structure. To further dissect the transcriptional mechanisms of costamere gene regulation and identify potential co-regulators of MEF2A, a bioinformatics analysis of transcription factor binding sites was performed using the proximal promoter regions of selected costamere genes. One of these predicted sites belongs to the early growth response (EGR) transcription factor family. The EGR1 isoform has been shown to be involved in a number of pathways in cardiovascular homeostasis and disease, making it an intriguing candidate MEF2 coregulator to further characterize. Here, we demonstrate that EGR1 interacts with MEF2A and is a potent and specific repressor of MEF2 transcriptional activity. Furthermore, we show that costamere gene expression in cardiomyocytes is dependent on EGR1 transcriptional activity. This study identifies a mechanism by which MEF2 activity can be modulated to ensure that costamere gene expression is maintained at levels commensurate with cardiomyocyte contractile activity.


Asunto(s)
Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Factores de Transcripción MEF2/metabolismo , Transcripción Genética/genética , Activación Transcripcional , Animales , Biología Computacional , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Células HEK293 , Humanos , Factores de Transcripción MEF2/genética , Miocitos Cardíacos/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Ratas
14.
J Biol Chem ; 290(2): 1256-68, 2015 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-25416778

RESUMEN

Skeletal muscle differentiation requires precisely coordinated transcriptional regulation of diverse gene programs that ultimately give rise to the specialized properties of this cell type. In Drosophila, this process is controlled, in part, by MEF2, the sole member of an evolutionarily conserved transcription factor family. By contrast, vertebrate MEF2 is encoded by four distinct genes, Mef2a, -b, -c, and -d, making it far more challenging to link this transcription factor to the regulation of specific muscle gene programs. Here, we have taken the first step in molecularly dissecting vertebrate MEF2 transcriptional function in skeletal muscle differentiation by depleting individual MEF2 proteins in myoblasts. Whereas MEF2A is absolutely required for proper myoblast differentiation, MEF2B, -C, and -D were found to be dispensable for this process. Furthermore, despite the extensive redundancy, we show that mammalian MEF2 proteins regulate a significant subset of nonoverlapping gene programs. These results suggest that individual MEF2 family members are able to recognize specific targets among the entire cohort of MEF2-regulated genes in the muscle genome. These findings provide opportunities to modulate the activity of MEF2 isoforms and their respective gene programs in skeletal muscle homeostasis and disease.


Asunto(s)
Diferenciación Celular/genética , Evolución Molecular , Factores de Transcripción MEF2/biosíntesis , Músculo Esquelético/crecimiento & desarrollo , Isoformas de Proteínas/biosíntesis , Animales , Células COS , Chlorocebus aethiops , Drosophila/genética , Drosophila/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica , Factores de Transcripción MEF2/antagonistas & inhibidores , Factores de Transcripción MEF2/genética , Mamíferos/genética , Mamíferos/crecimiento & desarrollo , Ratones , Desarrollo de Músculos/genética , Mioblastos/citología , Mioblastos/metabolismo , Isoformas de Proteínas/genética
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