New STAT3-FOXL2 pathway and its function in cancer cells

BMC Mol Cell Biol. 2019 Jun 20;20(1):17. doi: 10.1186/s12860-019-0206-3.

Abstract

Background: 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.

Results: In 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.

Conclusion: This 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.

Keywords: Cell apoptosis; STAT3-FOXL2 pathway; Signal transduction; Transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Binding Sites
  • Cell Survival
  • Forkhead Box Protein L2 / genetics
  • Forkhead Box Protein L2 / metabolism*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, LHRH / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / genetics
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • Transfection
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • FOXL2 protein, human
  • Forkhead Box Protein L2
  • GNRHR protein, human
  • RNA, Small Interfering
  • Receptors, LHRH
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TNF protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha