Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

Relav, Lauriane; Doghman, Mabrouka; Ruggiero, Carmen; Muzzi, João C. D.; Figueiredo, Bonald C.; Lalli, Enzo

doi:10.3390/ijms24043585

Cited by 10 publications

(14 citation statements)

References 123 publications

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“…Overexpression of transcription factor SF‐1 is a marker of malignancy in ACC 43 . An increased SF‐1 dosage in the H295R cell line considerably increases their invasive properties in vitro and in vivo 19,21 .…”

Section: Resultsmentioning

confidence: 99%

“…Overexpression of transcription factor SF-1 is a marker of malignancy in ACC. 43 An increased SF-1 dosage in the H295R cell line considerably increases their invasive properties in vitro and in vivo. 19,21 We have previously shown that FSCN1 knockdown or treatment with the FSCN1 small molecule inhibitor G2 impaired Matrigel invasion of H295R cells triggered by SF-1 overexpression.…”

Section: Inactivation Of Fscn1 Expression or Pharmacological Antagoni...mentioning

confidence: 99%

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FSCN1 as a new druggable target in adrenocortical carcinoma

Ruggiero

Tamburello

Rossini

et al. 2023

Intl Journal of Cancer

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Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high risk of relapse and metastatic spread. The actin-bundling protein fascin (FSCN1) is overexpressed in aggressive ACC and represents a reliable prognostic indicator. FSCN1 has been shown to synergize with VAV2, a guanine nucleotide exchange factor for the Rho/Rac GTPase family, to enhance the invasion properties of ACC cancer cells.Based on those results, we investigated the effects of FSCN1 inactivation by CRISPR/Cas9 or pharmacological blockade on the invasive properties of ACC cells, both in vitro and in an in vivo metastatic ACC zebrafish model. Here, we showed that FSCN1 is a transcriptional target for β-catenin in H295R ACC cells and that its inactivation resulted in defects in cell attachment and proliferation. FSCN1 knock-out modulated the expression of genes involved in cytoskeleton dynamics and cell adhesion. When Steroidogenic Factor-1 (SF-1) dosage was upregulated in H295R cells, activating their invasive capacities, FSCN1 knock-out reduced the number of filopodia, lamellipodia/ruffles and focal adhesions, while decreasing cell invasion in Matrigel. Similar effects were produced by the FSCN1 inhibitor G2-044, which also diminished the invasion of other ACC cell lines expressing lower levels of FSCN1 than H295R. In the zebrafish model, metastases formation was significantly reduced in FSCN1 knock-out cells and G2-044 significantly reduced the number of metastases formed by ACC cells. Our results indicate that FSCN1 is a new druggable target for ACC and provide the rationale for future clinical trials with FSCN1 inhibitors in patients with ACC.

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Section: Resultsmentioning

confidence: 99%

Section: Inactivation Of Fscn1 Expression or Pharmacological Antagoni...mentioning

confidence: 99%

FSCN1 as a new druggable target in adrenocortical carcinoma

Ruggiero

Tamburello

Rossini

et al. 2023

Intl Journal of Cancer

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“…Steroidogenic factor-1 (SF-1) is a member of the nuclear receptor superfamily first identified as a regulator of p450 enzymes, and is now recognised as a global regulator of steroidogenic gene expression. SF-1 has essential roles in adrenogonadal development and differentiation [181]. Multiple factors modulate SF-1 activity, including post-translational modification, ligand binding and gene dosage.…”

Section: Nuclear Ppins and Regulation Of Transcription Factorsmentioning

confidence: 99%

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

Vidalle,

Sheth,

Fazio

et al. 2023

Biomolecules

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Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are generated by the phosphorylation of the inositol head group of phosphatidylinositol (PtdIns). Different pools of PPIns are found at distinct subcellular compartments, which are regulated by an array of kinases, phosphatases and phospholipases. Six of the seven PPIns species have been found in the nucleus, including the nuclear envelope, the nucleoplasm and the nucleolus. The identification and characterisation of PPIns interactor and effector proteins in the nucleus have led to increasing interest in the role of PPIns in nuclear signalling. However, the regulation and functions of PPIns in the nucleus are complex and are still being elucidated. This review summarises our current understanding of the localisation, biogenesis and physiological functions of the different PPIns species in the nucleus.

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“…This fusion protein drives the expression of genes involved in cell proliferation and survival, leading to the development of Ewing sarcoma [1,2]. DAX1, also known as NR0B1, is a transcriptional regulator that plays a critical role in the development and function of several endocrine glands, including the adrenal gland and the hypothalamus [3]. Recent studies have also implicated DAX1 in the pathogenesis of Ewing sarcoma (ES), a rare type of bone cancer that primarily affects children and young adults.…”

Section: Introductionmentioning

confidence: 99%

Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies

Yasir

Park

Han

et al. 2023

IJMS

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Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1) is an orphan nuclear receptor encoded by the NR0B1 gene. The functional study showed that DAX1 is a physiologically significant target for EWS/FLI1-mediated oncogenesis, particularly Ewing Sarcoma (ES). In this study, a three-dimensional DAX1 structure was modeled by employing a homology modeling approach. Furthermore, the network analysis of genes involved in Ewing Sarcoma was also carried out to evaluate the association of DAX1 and other genes with ES. Moreover, a molecular docking study was carried out to check the binding profile of screened flavonoid compounds against DAX1. Therefore, 132 flavonoids were docked in the predicted active binding pocket of DAX1. Moreover, the pharmacogenomics analysis was performed for the top ten docked compounds to evaluate the ES-related gene clusters. As a result, the five best flavonoid-docked complexes were selected and further evaluated by Molecular Dynamics (MD) simulation studies at 100 ns. The MD simulation trajectories were evaluated by generating RMSD, hydrogen bond plot analysis, and interaction energy graphs. Our results demonstrate that flavonoids showed interactive profiles in the active region of DAX1 and can be used as potential therapeutic agents against DAX1-mediated augmentation of ES after in-vitro and in-vivo evaluations.

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Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

Cited by 10 publications

References 123 publications

FSCN1 as a new druggable target in adrenocortical carcinoma

FSCN1 as a new druggable target in adrenocortical carcinoma

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies

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