ECE2015 Oral Communications Nuclear receptors and signalling (5 abstracts)
An autoregulatory loop of nuclear corepressor 1 expression controls hepatocarcinoma invasion, growth and metastasis
Olaia Martinez-Iglesias 1 , Elvira Alonso-Merino 1 , Juan P Velasco-Martín 2 , Rosa M Martín-Orozco 1 , Enrique Luengo 1 , Rosa M García-Martín 3 , Inmaculada Ibanez de Caceres 4 , Agustin F Fernández 5 , Mario Fraga 5 , Pilar Gonzalez-Peramato 6 , Constantino Varona 7 , Jose Palacios 7 , Javier Regadera 2 & Ana Aranda 1
1Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain; 2Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; 3Departamento de Anatomía Patológica, Hospital Universitario 12 de Octubre, Madrid, Spain; 4Epigenetics Laboratory, INGEMM, Biomarkers and Experimental Therapeutics in Cancer, IdiPAZ, University Hospital La Paz, Madrid, Spain; 5Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain; 6Departamento de, Anatomía Patológica, Hospital Universitario La Paz, Madrid, Madrid, Spain; 7Departamento de Anatomía Patológica. Hospital Universitario Ramón y Cajal, Madrid, Spain.
Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. Genomic studies have shown the presence of inactivating mutations of the NCoR gene in human tumours and we have found that NCoR depletion with siRNA in hepatocarcinoma SK-hep1 cells enhances invasion, tumour growth and metastasis in nude mice, while expression of the thyroid hormone receptor β (TRβ) increases NCoR levels, repressing tumorigenesis. We have now analysed human hepatocarcinomas, finding that NCoR expression is significantly downregulated and that there is a good correlation with TRβ in the tumours, indicating the relevance of these observations in the patients. Strikingly, up to one month after siNCoR transfection, NCoR mRNA was still depleted in cells and tumours. This long-term depletion cannot be explained by DNA methylation of the regulatory CpG island of the NCoR promoter. In contrast, in chromatin immunoprecipitation (ChIP) assays we found increased recruitment of the corepressor SMRT and histone deacetylase 3 (HDAC3), as well as increase of the repressive histone marks H3K9me3 and H3K27me3. H3K9 methylation led to recruitment of the heterochromatin protein HP1γ, local heterochromatinisation, and exclusion of the stimulatory transcription factor SP1 from the promoter. Treatment of silenced cells with TSA, a HDAC inhibitor, caused NCoR gene re-expression, demonstrating the important role of histone deacetylation in long-term silencing of the NCoR gene. In conclusion, our data define NCoR as a potent tumour suppressor and as a potential therapeutic target in hepatocarcinomas. Our results also suggest that in the absence of NCoR mutations, a reduction of NCoR levels at a given point in time could be propagated for several generations to the daughter cells, enhancing their tumourigenic, invasive and metastatic capacity and contributing to tumour progression.
Disclosure: BFU2011-28058 from Ministerio de Economía y Competitividad; S2011/BMD-2328, from the Comunidad de Madrid and RD12/0036/0030 from the Instituto de Salud Carlos III and an AECC contract.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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