Belli Martina, Secchi Christian, Stupack Dwayne, Shimasaki Shunichi
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, California.
J Endocr Soc. 2019 Aug 29;3(11):2064-2081. doi: 10.1210/js.2019-00279. eCollection 2019 Nov 1.
Adult granulosa cell tumor (aGCT) is a rare type of ovarian cancer characterized by estrogen excess. Interestingly, only the single somatic mutation was found across virtually all aGCTs. We previously reported that FOXL2 stimulates CYP19 transcription synergistically with SMAD3, leading to elevated estradiol synthesis in a human granulosa cell line (HGrC1). This finding suggested a key role for FOXL2 in causing the typical estrogen overload in patients with aGCTs. We have now investigated the effect of FOXO1, a tumor suppressor, on activation by FOXL2 in the presence of SMAD3. Intriguingly, FOXO1 antagonized the positive, synergistic effect of FOXL2 and SMAD3 on CYP19 transcription. Similar to FOXL2, FOXO1 binds SMAD3 but not the proximal FOXL2 binding site (-199 bp) of the CYP19 promoter identified in our earlier studies. The results of a competitive binding assay suggested a possible underlying mechanism in which FOXO1 sequesters SMAD3 away from FOXL2, thereby negating the cooperative action of FOXL2 and SMAD3 in inducing CYP19 expression. To our knowledge, this study is the first to demonstrate the ability of FOXO1 to restore an altered CYP19 expression by FOXL2 and SMAD3 and provides insight as to why FOXO1 deficiency promotes GCT development in mice.
成人颗粒细胞瘤（aGCT）是一种罕见的卵巢癌，其特征是雌激素过多。有趣的是，几乎在所有aGCT中都只发现了单一的体细胞突变。我们之前报道过，FOXL2与SMAD3协同刺激CYP19转录，导致人颗粒细胞系（HGrC1）中雌二醇合成增加。这一发现表明FOXL2在导致aGCT患者典型的雌激素过载中起关键作用。我们现在研究了肿瘤抑制因子FOXO1在存在SMAD3的情况下对FOXL2激活作用的影响。有趣的是，FOXO1拮抗了FOXL2和SMAD3对CYP19转录的正向协同作用。与FOXL2相似，FOXO1与SMAD3结合，但不与我们早期研究中确定的CYP19启动子近端FOXL2结合位点（-199 bp）结合。竞争性结合试验的结果提示了一种可能的潜在机制，即FOXO1将SMAD3从FOXL2处隔离，从而消除FOXL2和SMAD3在诱导CYP19表达中的协同作用。据我们所知，本研究首次证明了FOXO1能够恢复FOXL2和SMAD3改变的CYP19表达，并为FOXO1缺陷促进小鼠颗粒细胞瘤发展的原因提供了见解。
