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1.
RNA ; 30(3): 281-297, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38191171

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3' endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of nontransformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional readthrough in replication-dependent histones, reduces core histone expression, destabilizes chromatin structure, and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.


Asunto(s)
Histonas , Neoplasias Pancreáticas , Humanos , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Poliadenilación , ARN Mensajero/genética , ARN Mensajero/metabolismo
2.
Epigenetics Chromatin ; 13(1): 6, 2020 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-32070414

RESUMEN

BACKGROUND: Maintaining a proper supply of soluble histones throughout the cell cycle is important to ensure chromatin and genome stability. Following their synthesis, histones undergo a series of maturation steps to prepare them for deposition onto chromatin. RESULTS: Here, we identify the lysine demethylase JMJD1B as a novel player in the maturation cascade that contributes to regulate histone provision. We find that depletion of JMJD1B increases the protein levels of the histone chaperone tNASP leading to an accumulation of newly synthesized histones H3 and H4 at early steps of the histone maturation cascade, which perturbs chromatin assembly. Furthermore, we find a high rate of JMJD1B mutations in cancer patients, and a correlation with genomic instability. CONCLUSIONS: Our data support a role for JMJD1B in fine-tuning histone supply to maintain genome integrity, opening novel avenues for cancer therapeutics.


Asunto(s)
Inestabilidad Genómica , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Procesamiento Proteico-Postraduccional , Células HeLa , Código de Histonas , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Mutación
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