Steroidogenic factor-1 (SF-1, NR5A1) is a transcription factor that plays an essential role in the development of adrenal glands and gonads. Multiple level regulation of SF-1 activity is exerted by interaction with cofactors, post-translational modifications and epigenetic gene expression regulation. Our studies involving both cell lines and transgenic mouse studies showed that an increased SF-1 dosage activates adrenocortical cell proliferation and causes adrenocortical neoplasia. By employing multiple genomic approaches, we defined different levels of regulation in transcriptome, miRNome and more recently on regulome exerted by SF-1 dosage. We identified new functional interactions between SF-1 and neuron-restrictive silencer factor/RE1-silencing transcription factor (NRSF/REST) suggesting that SF-1 has a broader role than initially thought in regulating tissue-specific gene expression programs.
We showed that SF-1 dosage differentially regulates the expression of numerous and distinct genes, involved in a variety of biological processes, suggesting that fine regulation of SF-1 dosage is a critical determinant of its action during adrenal development, function and tumourigenesis.
We identified fetal and adult testis expressed-1 (FATE1), a cancer testis antigen (CTA), as a new dosage-dependent target of SF-1. CTAs are emerging as attractive targets for therapeutic cancer vaccines due to their expression in tumors but not in normal tissues except testis. Our recent studies aim to better understand the role of FATE1 in tumor cellular metabolism, mitochondrial morphology and signaling and in drug resistance, potentially important for the aggressive phenotype of adrenocortical carcinoma.
Our project aims to investigate the involvement of these new SF-1 target genes in adrenal pathophysiology to improve the diagnostic of ACC and in the future to develop innovative strategies for cancer treatment.
Disclosure: This work has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259735 (ENS@T-CANCER).