Transcription factor 21 regulates expression of ERβ and SF-1 via upstream stimulatory factor-2 in endometriotic tissues

Pei Li Wu, Yan Zhou, Cheng Zeng, Xin Li, Zhao Tong Dong, Ying Fang Zhou, Serdar E Bulun, Qing Xue*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Steroidogenic factor-1 (SF-1, encoded by NR5A1) and estrogen receptor beta (ERβ encoded by ESR2), which are highly expressed in endometriotic stromal cells (ESCs), contribute to the pathogenesis of endometriosis, but the regulation mechanism remains largely unknown. Transcription factor 21 (TCF21) belongs to the helix-loop-helix (bHLH) family characterized by regulating gene expression via binding to E-box element. Here, we attempted to determine the molecular mechanism of TCF21 on SF-1 and ERβ expression in endometriosis. We found that TCF21 expression in ESCs was higher than that in endometrial stromal cells (EMs), and positively correlated with SF-1 and ERβ expression in ESCs. Since the importance of E-box element for NR5A1 promoter activity has been previously reported, we performed site-mutation and luciferase assay, revealing that the E-box sequence in the ESR2 promoter is also a critical element modulating ERβ expression. Upstream stimulatory factor 2 (USF2) is another bHLH factor implicated in transcriptional regulation. Further analyses elucidated that it is not TCF21, but USF2 exhibited higher binding affinities in ESCs to NR5A1 and ESR2 promoters than in EMs. Additionally, TCF21 knockdown significantly decreased the binding activities of USF2 to NR5A1 and ESR2 promoters via disruption of the TCF21-USF2 complex. Meanwhile, manipulating TCF21 expression significantly affected MMP9 and cyclinD1 expression, as wells as proliferation and invasion of ESCs. Moreover, TCF21 depletion in endometriotic xenografts reduced SF-1 and ERβ expression, abrogating ectopic lesion growth in mice. Cumulatively, a critical role of TCF21 in the pathogenesis of endometriosis is demonstrated, suggesting a potential druggable target for future therapy.

Original languageEnglish (US)
Pages (from-to)706-717
Number of pages12
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1861
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

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Keywords

  • ERβ
  • Endometriosis
  • SF-1
  • Transcription factor 21
  • USF2

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics

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