Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-01, Vol.113 (3), p.E328-E337
• Main Authors: Martínez-Iglesias, Olaia A., Alonso-Merino, Elvira, Gómez-Rey, Sara, Velasco-Martín, Juan Pedro, Orozco, Rosa Martín, Luengo, Enrique, Martín, Rosa García, de Cáceres, Inmaculada Ibáñez, Fernández, Agustín F., Fraga, Mario F., González-Peramato, Pilar, Varona, Constantino, Palacios, José, Regadera, Javier, Aranda, Ana
• Format: Article
• Language: English
• Subjects: Aged; Animals; Biological Sciences; Breast cancer; Breast Neoplasms - genetics; Cell Line, Tumor; Cell Proliferation; Correlation analysis; DNA Methylation - genetics; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes; Heterochromatin - metabolism; Homeostasis; Hormones; Humans; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Metastasis; Mice, Nude; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Nuclear Receptor Co-Repressor 1 - genetics; Nuclear Receptor Co-Repressor 1 - metabolism; Nuclear Receptor Co-Repressor 2 - metabolism; PNAS Plus; Promoter Regions, Genetic - genetics; RNA, Small Interfering - metabolism; Rodents; Thyroid; Thyroid Hormone Receptors beta; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1520469113

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.