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1.
Mol Cell ; 83(13): 2206-2221.e11, 2023 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-37311463

RESUMEN

Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation.


Asunto(s)
Cromatina , Histonas , Ratones , Animales , Cromatina/genética , Histonas/metabolismo , Lisina/metabolismo , Factores de Transcripción/metabolismo , Regulación de la Expresión Génica , Acetilación
2.
Proc Natl Acad Sci U S A ; 115(31): 7949-7954, 2018 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-30012592

RESUMEN

The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Proteínas de Ciclo Celular , Línea Celular Tumoral , Femenino , Humanos , Subunidad 1 del Complejo Mediador/genética , Subunidad 1 del Complejo Mediador/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismo
3.
Nat Commun ; 14(1): 378, 2023 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-36690674

RESUMEN

BRD4-NUT, a driver fusion mutant in rare and highly aggressive NUT carcinoma, acts in aberrant transcription of anti-differentiation genes by recruiting histone acetyltransferase (HAT) p300 and promoting p300-driven histone hyperacetylation and nuclear condensation in chromatin. However, the molecular basis of how BRD4-NUT recruits and activates p300 remains elusive. Here, we report that BRD4-NUT contains two transactivation domains (TADs) in NUT that bind to the TAZ2 domain in p300. Our NMR structures reveal that NUT TADs adopt amphipathic helices when bound to the four-helical bundle TAZ2 domain. The NUT protein forms liquid-like droplets in-vitro that are enhanced by TAZ2 binding in 1:2 stoichiometry. The TAD/TAZ2 bipartite binding in BRD4-NUT/p300 triggers allosteric activation of p300 and acetylation-driven liquid-like condensation on chromatin that comprise histone H3 lysine 27 and 18 acetylation and transcription proteins BRD4L/S, CDK9, MED1, and RNA polymerase II. The BRD4-NUT/p300 chromatin condensation is key for activating transcription of pro-proliferation genes such as ALX1, resulting ALX1/Snail signaling and epithelial-to-mesenchymal transition. Our study provides a previously underappreciated structural mechanism illuminating BRD4-NUT's bipartite p300 recruitment and activation in NUT carcinoma that nucleates a feed-forward loop for propagating histone hyperacetylation and chromatin condensation to sustain aberrant anti-differentiation gene transcription and perpetual tumor cell growth.


Asunto(s)
Carcinoma , Proteínas de Ciclo Celular , Cromatina , Proteínas de Neoplasias , Proteínas Nucleares , Humanos , Acetilación , Carcinoma/metabolismo , Carcinoma/patología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Proteínas de Neoplasias/metabolismo
4.
Oncogene ; 41(23): 3251-3262, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35513563

RESUMEN

CUB domain-containing protein 1 (CDCP1), a transmembrane protein with tumor pro-metastatic activity, is highly expressed in late-stage and castrate-resistant prostate cancer (CRPC). However, the molecular mechanism driving CDCP1 overexpression in CRPC progress remains elusive. Here we report that transcription cofactors BRD4 and CBP/p300 co-regulate transcriptional expression of CDCP1 in CRPC tumorigenesis. In contrast to androgen receptor (AR) in CRPC, increased expression of BRD4 and CBP/p300 is strongly correlated with CDCP1 gene amplification. Combined knockdown or dual-inhibition of BRD4 and CBP/p300 down-regulated CDCP1 transcription and downstream PI3K/AKT and/or SRC/MAPK signaling pathways in CRPC cells much more so than single-protein perturbation. Our biochemical and structural analyses further showed that NEO2734, a dual-inhibitor targeting BRD4 and p300 bromodomains exhibits greater efficacy than single inhibitors for BRD4 or CBP/p300 in suppressing CDCP1 transcriptional expression and its downstream signaling pathways in CRPC cell proliferation and metastasis. Our study illustrates that targeting CDCP1 through dual-inhibition of BRD4 and CBP/p300 represents a synergistic therapeutic strategy for new treatment of CRPC.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Antígenos de Neoplasias , Bencimidazoles , Moléculas de Adhesión Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Humanos , Masculino , Proteínas Nucleares/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Piridonas , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética
5.
Front Oncol ; 12: 906807, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36033518

RESUMEN

ASH1L is a member of the Trithorax-group protein and acts as a histone methyltransferase for gene transcription activation. It is known that ASH1L modulates H3K4me3 and H3K36me2/3 at its gene targets, but its specific mechanism of histone recognition is insufficiently understood. In this study, we found that the ASH1L plant homeodomain (PHD) finger interacts with mono-, di-, and trimethylated states of H3K4 peptides with comparable affinities, indicating that ASH1L PHD non-selectively binds to all three methylation states of H3K4. We solved nuclear magnetic resonance structures picturing the ASH1L PHD finger binding to the dimethylated H3K4 peptide and found that a narrow binding groove and residue composition in the methylated-lysine binding pocket restricts the necessary interaction with the dimethyl-ammonium moiety of K4. In addition, we found that the ASH1L protein is overexpressed in castrate-resistant prostate cancer (PCa) PC3 and DU145 cells in comparison to PCa LNCaP cells. The knockdown of ASH1L modulated gene expression and cellular pathways involved in apoptosis and cell cycle regulation and consequently induced cell cycle arrest, cell apoptosis, and reduced colony-forming abilities in PC3 and DU145 cells. The overexpression of the C-terminal core of ASH1L but not the PHD deletion mutant increased the overall H3K36me2 level but had no effect on the H3K4me2/3 level. Overall, our study identifies the ASH1L PHD finger as the first native reader that non-selectively recognizes the three methylation states of H3K4. Additionally, ASH1L is required for the deregulation of cell cycle and survival in PCas.

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