Mutant FOXL2^C134W Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors.

ABSTRACT: The mutant protein FOXL2^C134W is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2^C134W contributes to tumorigenesis is not known. Here, we show that mutant FOXL2^C134W acquires the ability to bind SMAD4, forming a FOXL2^C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2^C134W mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2^C134W also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in stron

SUBMITTER: Weis-Banke SE 

PROVIDER: S-EPMC8278322 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature