title: Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFβ, and Wnt/β-catenin signaling in adrenocortical carcinoma cells.
abstract: The orphan nuclear receptor Steroidogenic Factor-1 (SF-1, NR5A1) is a critical regulator of development and homeostasis of the adrenal cortex and gonads. We recently showed that a complex containing E3 ubiquitin ligase RNF31 and the known SF-1 corepressor DAX-1 (NR0B1) interacts with SF-1 on target promoters and represses transcription of steroidogenic acute regulatory protein (StAR) and aromatase (CYP19) genes. To further evaluate the role of SF-1 in the adrenal cortex and the involvement of RNF31 in SF-1-dependent pathways, we performed genome-wide gene-expression analysis of adrenocortical NCI-H295R cells where SF-1 or RNF31 had been knocked down using RNA interference. We find RNF31 to be deeply connected to cholesterol metabolism and steroid hormone synthesis, strengthening its role as an SF-1 coregulator. We also find intriguing evidence of negative crosstalk between SF-1 and both transforming growth factor (TGF) β and Wnt/β-catenin signaling. This crosstalk could be of importance for adrenogonadal development, maintenance of adrenocortical progenitor cells and the development of adrenocortical carcinoma. Finally, the SF-1 gene profile can be used to distinguish malignant from benign adrenocortical tumors, a finding that implicates SF-1 in the development of malignant adrenocortical carcinoma.
authors.affiliation: Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Ehrlund
authors.forename: Philip
authors.initials: P
authors.lastname: Jonsson
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Vedin
authors.forename: Cecilia
authors.initials: C
authors.lastname: Williams
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Eckardt
authors.initials: E
authors.lastname: Treuter
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism*; D018268:Adrenocortical Carcinoma / Q000378:metabolism*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005576:Colforsin; D019295:Computational Biology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques / Q000379:methods; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis; D006801:Humans; D046228:Microarray Analysis; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D012739:Gonadal Steroid Hormones; C515057:NR5A1 protein, human; D034741:RNA, Small Interfering; D054339:Steroidogenic Factor 1; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D005576:Colforsin; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases; D001973:Bromodeoxyuridine