Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a

Abstract

Abstract. We previously identified FOXA1 as a tumorsuppressor 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.

Comprehensive bioinformatics analysis reveals the significance of forkhead box family members in pancreatic adenocarcinoma

“…In our results, the relationship between FOXA1 and aging is contradictory ( Figure 6C , 6D ). Jingyun Wang et al found that FOXA1 could induce endometrial cancer cell senescence by interacting with p16INK4a [ 25 ]. The true relationship between FOXs and senescence in PAAD still needs further experimental validation.…”

FOXA1 Expression by Immunohistochemistry in Carcinosarcomas of the Endometrium and Ovary/Fallopian Tube

“…It has been proposed that FOXA1 is a tumor suppressor in endometrial cancer 7,8, through modulation of the proliferation and migration of endometrial cancer cells 7, and that it has a possible interaction with ER 8. It has been also suggested that FOXA1 promotes cell senescence in endometrial cancer by interaction with p16 13. FOXA1 is overexpressed in ER-positive endometrial cancer cell lines, and in both normal endometrium and well-differentiated endometrial cancer tissues; also, the forced expression of FOXA1 inhibits endometrial cancer cell proliferation, whereas FOXA1 depletion promotes cell viability and is associated with tumorigenesis 8.…”

FOXA1 Suppresses the Growth, Migration, and Invasion of Nasopharyngeal Carcinoma Cells through Repressing miR-100-5p and miR-125b-5p

“…It has been shown that FOXA1 is upregulated in both replicative and oncogene-induced senescent cells [18]. Forced expression of FOXA1 in endometrial cancer cells leads to cellular senescence [24]. Sustained activation of Ras is known to be cause of oncogene-induced senescence [25,26].…”