Abstract
BackgroundThe forkhead transcription factor (FOXL2) plays a crucial role in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), sex determination, ovary growth and development, and cell cycle regulation. Emerging investigations have focused on the downstream targets of FOXL2, while little is known about its upstream regulation.ResultsIn this study, we show that FOXL2 could be regulated by STAT3 in cancer cells and that STAT3 binds to FOXL2 at the 5′- GCCTGATGTTTGTCTTCCCAGTCTGTGGCAA-3′ site using EMSA and ChIP. We further found that knockdown of STAT3 or FOXL2 could significantly induce cancer cell apoptosis, indicating the importance of these two genes in cancer cell growth and apoptosis. Our data also indicated that the increased apoptotic cell rate may be caused by changes in apoptosis-related genes, such as TNF, TRAIL and GnRHR.ConclusionThis study presents a new upstream regulator of FOXL2 and demonstrats that this new STAT3-FOXL2 pathway has an important function in HeLaHeLa cell apoptosis, providing new insights regarding the targeting of FOXL2 for cancer prevention and treatment.
Highlights
The forkhead transcription factor (FOXL2) plays a crucial role in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), sex determination, ovary growth and development, and cell cycle regulation
We mainly focus on upregulation of Forkhead box L2 (FOXL2), the chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) results demonstrated that there are accurate Signal transducer and activator of transcription 3 (STAT3) binding sequences (5′-GCCTGATGTTTGTCTTCCCAGTCTG TGGCAA-3′) in the promoter region of FOXL2 for the first time
Accurate binding sequence of STAT3 in the promoter region of FOXL2 In our previous paper, we demonstrated that the luciferase activity fused to the promoter of FOXL2 was significantly downregulated when HeLa cells were treated with a STAT3 inhibitor, suggesting that STAT3 activated the FOXL2 gene
Summary
The forkhead transcription factor (FOXL2) plays a crucial role in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), sex determination, ovary growth and development, and cell cycle regulation. Emerging investigations have focused on the downstream targets of FOXL2, while little is known about its upstream regulation. FOXL2 is a single-exon gene that encodes a 376 amino acids protein in humans that contains a 110-amino-acid DNAbinding forkhead domain (FHD) and a polyalanine (poly-Ala) tract of 14 residues of unknown function [1], and this gene is preferentially expressed in the ovary, the eyelids and the pituitary gland [2]. Many researchers have focused on the downstream targets of FOXL2 as a major transcriptional factor. The potential transcriptional targets of FOXL2 include cell cycle related genes and stress response related genes in humans [12]. Research papers investigating the upstream regulation of FOXL2 are still limited and restrict the further study of the biological functions of the gene
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