NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor.

Bury, Marina; Le Calvé, Benjamin; Lessard, Frédéric; Dal Maso, Thomas; Saliba, James; Michiels, Carine; Ferbeyre, Gerardo; Blank, Volker

Bury, Marina; Le Calvé, Benjamin; Lessard, Frédéric; Dal Maso, Thomas; Saliba, James; Michiels, Carine; Ferbeyre, Gerardo; Blank, Volker.

Afiliación

Bury M; Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada.
Le Calvé B; Department of Biochemistry, University of Montreal, Montreal, QC H3C 3J7, Canada.
Lessard F; Department of Biochemistry, University of Montreal, Montreal, QC H3C 3J7, Canada.
Dal Maso T; Department of Chemistry, Namur Medicine and Drug Innovation Center (NAMEDIC-NARILIS), University of Namur, 5000 Namur, Belgium.
Saliba J; Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada.
Michiels C; URBC-NARILIS, University of Namur, 5000 Namur, Belgium.
Ferbeyre G; Department of Biochemistry, University of Montreal, Montreal, QC H3C 3J7, Canada.
Blank V; Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada; Department of Medicine, McGill University, Montreal, QC H3T 1E2, Canada; Department of Physiology, McGill University, Montreal, QC H3T 1E2, Canada. Electronic address: volker.blank@mcgill.ca.

Cell Rep ; 29(6): 1469-1481.e9, 2019 11 05.

Article en En | MEDLINE | ID: mdl-31693889

RESUMEN

Constitutive nuclear factor κB (NF-κB) activation is a hallmark of colon tumor growth. Cyclin-dependent kinases (CDKs) are critical cell-cycle regulators, and inhibition of CDK activity has been used successfully as anticancer therapy. Here, we show that the NFE2L3 transcription factor functions as a key regulator in a pathway that links NF-κB signaling to the control of CDK1 activity, thereby driving colon cancer cell proliferation. We found that NFE2L3 expression is regulated by the RELA subunit of NF-κB and that NFE2L3 levels are elevated in patients with colon adenocarcinoma when compared with normal adjacent tissue. Silencing of NFE2L3 significantly decreases colon cancer cell proliferation in vitro and tumor growth in vivo. NFE2L3 knockdown results in increased levels of double homeobox factor 4 (DUX4), which functions as a direct inhibitor of CDK1. The discovered oncogenic pathway governing cell-cycle progression may open up unique avenues for precision cancer therapy.

Asunto(s)

Adenocarcinoma/metabolismo; Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo; Proteína Quinasa CDC2/antagonistas & inhibidores; Neoplasias del Colon/metabolismo; Proteínas de Homeodominio/metabolismo; Adenocarcinoma/genética; Adenocarcinoma/mortalidad; Adenocarcinoma/secundario; Animales; Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética; Proteína Quinasa CDC2/genética; Proteína Quinasa CDC2/metabolismo; Puntos de Control del Ciclo Celular/genética; Línea Celular Tumoral; Proliferación Celular/genética; Secuenciación de Inmunoprecipitación de Cromatina; Neoplasias del Colon/genética; Neoplasias del Colon/mortalidad; Neoplasias del Colon/patología; Regulación Neoplásica de la Expresión Génica/genética; Técnicas de Silenciamiento del Gen; Silenciador del Gen; Proteínas de Homeodominio/genética; Humanos; Espectrometría de Masas; Ratones; Ratones Desnudos; FN-kappa B/metabolismo; ARN Interferente Pequeño; Transducción de Señal/genética; Factor de Transcripción ReIA/genética; Factor de Transcripción ReIA/metabolismo; Trasplante Heterólogo

Palabras clave

CDK inhibitor; CDK1; DUX4; NF-κB; NFE2L3; cell cycle; colorectal cancer

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenocarcinoma / Proteína Quinasa CDC2 / Neoplasias del Colon / Proteínas de Homeodominio / Factores de Transcripción con Cremalleras de Leucina de Carácter Básico Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2019 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos

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