ProjectDiscovery of the key role of SF-1 transcription factor overexpression and its target genes in the pathogenesis of adrenocortical tumors
About
NR5A1/SF-1 (Steroidogenic Factor-1), a transcription factor belonging to the nuclear receptor family, plays a key role in adrenal and gonad development and the regulation of steroidogenesis. Our previous studies have revealed that SF-1 overexpression triggers increased proliferation in human adrenocortical carcinoma (ACC) cells and induces adrenocortical tumorigenesis in transgenic mice. S-1 (Doghman et al., 2007). Furthermore, SF-1 overexpression represents a stage-independent negative prognostic marker in patients with ACC (Sbiera et al., 2010). SF-1 inverse agonists can neutralize the effects of SF-1 overexpression on ACC cell proliferation, indicating that this transcription factor represents a novel therapeutic target in these cancers (Doghman et al., 2009).
An increased dose of SF-1 in ACC cells induces significant changes in their gene expression, modulating the expression of a variety of genes involved in several physiological processes and signaling pathways. Remarkably, some of these changes reflect similar alterations in gene expression found in ACC compared to benign tumors and normal adrenal cortex tissue (Doghman). et al., 2007a and 2007b). These results validated the use of our cell model as a platform for discovering new gene products involved in defining the malignant phenotype in ACC. We used our cell model to:
– to identify the SF-1 regulome and the dose-dependent transcriptional regulation mechanisms of this transcription factor. We have shown that SF-1 regulates different gene classes depending on its dosage. Our work has revealed unexpected functional interactions between this transcription factor and the Neuron-Restrictive Silencer Factor/RE1-Silencing Transcription factor (NRSF/REST) and shown that NRSF/REST has a novel function in the regulation of gene expression in steroidogenic cells (Doghman). et al., 2013);
– to characterize the cellular function of SF-1 dose-dependent target gene products in order to understand the mechanisms by which an increase in SF-1 dose triggers adrenocortical tumorigenesis. Here are two examples:
– FATE1 is a gene coding for an antigen expressed in the testicle and in several types of cancer (cancer-testis antigenOur studies have shown that FATE1 is an endoplasmic reticulum (ER) protein enriched in mitochondria-associated membranes (MAMs). FATE1 is a novel modulator of the ER-mitochondria distance and its role is to decrease their sensitivity to Ca2+-dependent proapoptotic stimuli2+ mitochondrial and mitotane, the most widely used chemotherapy drug in the treatment of ACC. There is a strong negative correlation between FATE1 expression and recurrence and overall survival in patients with ACC (Doghman-Bouguerra). et al., 2016);
– VAV2 VAV2 encodes a guanine nucleotide exchange factor (GEF) for small Rho family GTPases, which control cytoskeletal remodeling and the invasive capacity of cancer cells. We have demonstrated that VAV2 plays a crucial role in increasing the invasive properties of ACC cells following increased SF-1 levels. Furthermore, VAV2 expression in the tumor is a stage-independent prognostic factor in ACC patients (Ruggiero). et al., 2017).