title: Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a.
abstract: We previously identified FOXA1 as a tumor-suppressor in EC cells. In the present study, we sought to delineate the different roles of FOXA1 associated with cell senescence and further investigated the correlation between FOXA1 and p16INK4a in the progression of EC. Using reverse transcription-quantitative PCR (RT-qPCR), we found that FOXA1 expression was significantly downregulated in EC cells compared to that in normal endometrial cells. Functionally, senescence‑associated β-galactosidase staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic and Transwell assays showed that in addition to acting as a pioneer factor, FOXA1 was significantly upregulated in senescent EC cells. Furthermore, restoration of FOXA1 expression triggered multiple steps of cellular senescence in EC cells and activated p16INK4a expression. All of these findings indicate that FOXA1 promotes cell senescence in EC by interaction with p16INK4a, possibly via the AKT pathway. Notably, a selective PI3K inhibitor raised the possibility that FOXA1‑induced senescence is associated with the AKT pathway in EC cells. Collectively, the present study provides a conceivable molecular mechanism by which cell senescence acts as the barrier to EC, and is regulated by FOXA1-induced p16INK4a expression. This may be a newly identified regulatory mechanism of cell senescence in EC.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, P.R. China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, P.R. China.
authors.forename: Yiding
authors.initials: Y
authors.lastname: Bian
authors.affiliation: Department of Obstetrics and Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, P.R. China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D001616:beta-Galactosidase