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.

<i>FOXL2 </i>Impairment in Human Disease

“…Differences have been found between wild-type and mutant FOXL2 however, such as increased induction of the target aromatase by the mutation [53] and a lower capacity of the mutation to induce apoptosis, thereby compromising cell death [47,48,53]. A very recent study by Benayoun et al [54] suggested that this mutation might interfere with the capacity of FOXL2 to modulate the cell cycle.…”

Adult granulosa cell tumours (GCT): Clinicopathological outcomes including FOXL2 mutational status and expression

“…A recurring somatic mutation in this gene has been described as a potential 'driver' in the pathogenesis of adult-type GCTs [7]. A few studies have investigated the effect of the mutant allele, including studying its transcriptional targets [8][9][10][11][12]. The identification of a recurring mutation reported to be present in up to 94-97% of adult-type tumours may serve as another diagnostic tool for GCTs, alongside traditional pathological and immunohistochemical features.…”

Roles of SIRT1 in granulosa cell apoptosis during the process of follicular atresia in porcine ovary

“…It has been reported that SIRT1 protein was expressed in mouse ovarian tissues (Morita et al, 2012), human luteinized granulosa cells (Benayoun et al, 2011) and bovine oocytes (Ghinis-Hozumi et al, 2011). The present study showed that SIRT1 protein was widely expressed in porcine ovary.…”