title: Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase.
abstract: FOXL2 is a transcription factor that is essential for ovarian function and maintenance, the germline mutations of which are responsible for the Blepharophimosis Ptosis Epicanthus-inversus Syndrome (BPES), often associated with premature ovarian failure. Recent evidence has linked FOXL2 downregulation or somatic mutation (p.Cys134Trp) to cancer, although underlying molecular mechanisms remain unclear. Using a functional genomic approach, we find that FOXL2 modulates cell-cycle regulators in a way which tends to induce G1 arrest. Indeed, FOXL2 upregulation promotes cell accumulation in G1 phase and protects cells from oxidative damage, notably by promoting oxidized DNA repair and by increasing the amounts of anti-oxidant agent glutathione. In agreement with clinical observations, we find that FOXL2-mutated versions leading to BPES along with ovarian dysfunction mostly fail to transactivate cell-cycle and DNA repair targets, whereas mutations leading to isolated craniofacial defects (and normal ovarian function) activate them correctly. Interestingly, these assays revealed a mild promoter-specific hypomorphy of the tumor-associated mutation (p.Cys134Trp). Finally, the SIRT1 deacetylase suppresses FOXL2 activity on targets linked to cell-cycle and DNA repair in a dose-dependent manner. Accordingly, we find that SIRT1 inhibition by nicotinamide limits proliferation, notably by increasing endogenous FOXL2 amount/activity. The body of evidence presented here supports the idea that FOXL2 plays a key role in granulosa cell homeostasis, the failure of which is central to ovarian ageing and tumorigenesis. As granulosa cell tumors respond poorly to conventional chemotherapy, our findings on the deacetylase inhibitor nicotinamide provide an interesting option for targeted therapy.
authors.affiliation: CNRS UMR 7592, Institut Jacques Monod, Equipe Génétique et Génomique du Développement Gonadique 75205 Paris Cedex 13, France.
authors.forename: Bérénice A
authors.initials: BA
authors.lastname: Benayoun
authors.forename: Adrien B
authors.initials: AB
authors.lastname: Georges
authors.forename: David
authors.initials: D
authors.lastname: L'Hôte
authors.forename: Noora
authors.initials: N
authors.lastname: Andersson
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dipietromaria
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Todeschini
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caburet
authors.forename: Claude
authors.initials: C
authors.lastname: Bazin
authors.forename: Mikko
authors.initials: M
authors.lastname: Anttonen
authors.forename: Reiner A
authors.initials: RA
authors.lastname: Veitia
mesh_terms: D002453:Cell Cycle; D002460:Cell Line; D004260:DNA Repair; D015536:Down-Regulation; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1