Research Papers:

SET oncoprotein accumulation regulates transcription through DNA demethylation and histone hypoacetylation

Luciana O. Almeida, Marinaldo P.C. Neto, Lucas O. Sousa, Maryna A. Tannous, Carlos Curti and Andreia M. Leopoldino _

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Oncotarget. 2017; 8:26802-26818. https://doi.org/10.18632/oncotarget.15818

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Luciana O. Almeida1,3, Marinaldo P.C. Neto1, Lucas O. Sousa1, Maryna A. Tannous1, Carlos Curti2, Andreia M. Leopoldino1,4

1Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

2Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

3Department of Genetics and Evolution, Federal University of São Carlos, São Carlos, SP, Brazil

4CEPID-FAPESP, Center for Cell Based Therapy, Hemotherapy Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil

Correspondence to:

Andreia M. Leopoldino, email: andreiaml@usp.br

Keywords: chromatin, HNSCC, SET protein, histone acetylation, active DNA demethylation

Received: June 30, 2016     Accepted: February 20, 2017     Published: March 01, 2017


Epigenetic modifications are essential in the control of normal cellular processes and cancer development. DNA methylation and histone acetylation are major epigenetic modifications involved in gene transcription and abnormal events driving the oncogenic process. SET protein accumulates in many cancer types, including head and neck squamous cell carcinoma (HNSCC); SET is a member of the INHAT complex that inhibits gene transcription associating with histones and preventing their acetylation. We explored how SET protein accumulation impacts on the regulation of gene expression, focusing on DNA methylation and histone acetylation. DNA methylation profile of 24 tumour suppressors evidenced that SET accumulation decreased DNA methylation in association with loss of 5-methylcytidine, formation of 5-hydroxymethylcytosine and increased TET1 levels, indicating an active DNA demethylation mechanism. However, the expression of some suppressor genes was lowered in cells with high SET levels, suggesting that loss of methylation is not the main mechanism modulating gene expression. SET accumulation also downregulated the expression of 32 genes of a panel of 84 transcription factors, and SET directly interacted with chromatin at the promoter of the downregulated genes, decreasing histone acetylation. Gene expression analysis after cell treatment with 5-aza-2′-deoxycytidine (5-AZA) and Trichostatin A (TSA) revealed that histone acetylation reversed transcription repression promoted by SET. These results suggest a new function for SET in the regulation of chromatin dynamics. In addition, TSA diminished both SET protein levels and SET capability to bind to gene promoter, suggesting that administration of epigenetic modifier agents could be efficient to reverse SET phenotype in cancer.

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