Abstract
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.
Highlights
Epigenetics refers to heritable changes in gene expression not related to changes in the DNA sequence [1]; they occur primarily through DNA methylation and histone post-translational modifications
As the oncogene SET is a potent inhibitor of the tumour suppressor PP2A [16, 17], and inhibits other tumour suppressors such as PTEN [18] and TP53 [19], we examined how SET accumulation affects DNA methylation using a panel of known tumour suppressor genes by means of EpiTect Methyl qPCR arrays (Figure 1A)
SET-accumulating cells displayed decreased average DNA methylation (Figure 1B - red arrows), while the head and neck squamous cell carcinoma (HNSCC) cell lines with knocked down SET displayed increased average DNA methylation (Figure 1B – green arrows); these findings suggest that SET accumulation influences DNA methylation
Summary
Epigenetics refers to heritable changes in gene expression not related to changes in the DNA sequence [1]; they occur primarily through DNA methylation and histone post-translational modifications. Epigenetic changes have been associated with specific patterns of gene expression and are early events in different cancer types, including head and neck squamous cell carcinoma (HNSCC) [2]. DNA demethylation occurs through an active mechanism, independent of cell division, which is mediated by enzymes of the TET family. These enzymes firstly modify methylated cytosine, which is subsequently replaced by the DNA repair machinery [5, 6]
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