Abstract
Aberrant re-activation of transcription factors occurs frequently in cancer. Recently, we found the basic helix-loop-helix transcription factors DEC1 and DEC2 significantly up-regulated in a model of highly aggressive thyroid cancer, raising the hypothesis that these factors might be part of the program driving progression of these tumors. Here, we investigated for the first time the function of DEC1 and DEC2 in thyroid cancer. Using both gain- and loss-of-function approaches, we showed that DEC1 more than DEC2 sustains progression of thyroid cancer by promoting cell growth and invasiveness. We demonstrated that DEC1 controls NOTCH1 expression and that the interplay with the NOTCH pathway is relevant for DEC1 function in thyroid cancer. We confirmed this observation in vivo showing that DEC1 expression is a specific feature of tumor cells, that this transcription factor is significantly over-expressed in all major thyroid cancer histotypes and that its expression correlated with NOTCH1 in these tumors. Finally, we performed RNA-sequencing to define the DEC1-associated gene expression profile in thyroid cancer cells and we discovered that DEC1 drives the expression of many cell cycle-related genes, uncovering a potential new function for this transcription factor in cancer.
Highlights
Thyrocyte-derived cancers are the most common malignancies of the endocrine system[1]
DEC1 and DEC2 are expressed in aggressive thyroid cancer models Recently, we found DEC1 and DEC2 significantly upregulated in a genetically modified model of thyroid cancer that acquired feature of aggressiveness (BCPAP_Id1A)[6]
DEC1 was significantly overexpressed in all cancer cell lines analyzed with the exception of Cal[62] that expressed low levels of both DEC1 and DEC2
Summary
Thyrocyte-derived cancers are the most common malignancies of the endocrine system[1]. These tumors are classified as differentiated (DTC), poorly-differentiated (PDTC), and anaplastic thyroid carcinomas (ATC)[2,3]. We reported that the transcription regulator Id1 promotes aggressiveness of thyroid carcinomas by regulating the expression of genes involved in epithelial to mesenchymal transition (EMT), invasion, and migration[6]. Several transcription factors (TFs) were under the control of Id1 in thyroid cancer including the basic HelixLoop-Helix (bHLH) proteins DEC1 and DEC27. DEC1 and DEC2 are members of the Hairy/E(spl)/HES subgroup within the bHLH TFs family[8,9,10,11]
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