title: Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis.
abstract: Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
authors.forename: Olaia A
authors.initials: OA
authors.lastname: Martínez-Iglesias
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
authors.forename: Elvira
authors.initials: E
authors.lastname: Alonso-Merino
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
authors.forename: Sara
authors.initials: S
authors.lastname: Gómez-Rey
authors.affiliation: Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Velasco-Martín
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
authors.forename: Rosa
authors.initials: R
authors.lastname: Martín Orozco
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
authors.forename: Enrique
authors.initials: E
authors.lastname: Luengo
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain;
authors.forename: Rosa
authors.initials: R
authors.lastname: García Martín
authors.affiliation: Epigenetics Laboratory, Instituto de Genética Médica y Molecular, Biomarkers and Experimental Therapeutics in Cancer, Instituto de Investigación, Hospital Universitario La Paz, 28046 Madrid, Spain;
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ibáñez de Cáceres
authors.affiliation: Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33006 Principado de Asturias, Spain;
authors.forename: Agustín F
authors.initials: AF
authors.lastname: Fernández
authors.affiliation: Nanomaterials and Nanotechnology Research Center (Centro de Investigación en Nanomateriales y Nanotecnología-Consejo Superior de Investigaciones Científicas), Universidad de Oviedo, 33940 Principado de Asturias, Spain;
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario La Paz, 28046 Madrid, Spain;
authors.forename: Pilar
authors.initials: P
authors.lastname: González-Peramato
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Instituto de Investigación Sanitaria Ramón y Cajal (Instituto Ramón y Cajal de Investigación Sanitaria), Universidad de Alcalá, 28034 Madrid, Spain.
authors.forename: Constantino
authors.initials: C
authors.lastname: Varona
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Instituto de Investigación Sanitaria Ramón y Cajal (Instituto Ramón y Cajal de Investigación Sanitaria), Universidad de Alcalá, 28034 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.affiliation: Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
authors.forename: Javier
authors.initials: J
authors.lastname: Regadera
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain; aaranda@iib.uam.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Aranda
mesh_terms: D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006570:Heterochromatin / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics* / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta; D023041:Xenograft Model Antitumor Assays
chemical_list: D006570:Heterochromatin; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D034741:RNA, Small Interfering; D037042:Thyroid Hormone Receptors beta
keywords: metastasis; nuclear corepressor 1; thyroid hormone receptor; transcription; tumor growth