Transcriptional repressor GATA binding 1-mediated repression of SRY-box 2 expression suppresses cancer stem cell functions and tumor initiation

J Biol Chem. 2018 Nov 30;293(48):18646-18654. doi: 10.1074/jbc.RA118.003983. Epub 2018 Oct 12.

Abstract

Cancer stem cells (CSCs) have been reported in a variety of cancers. SRY-box 2 (SOX2) is a member of the SOX family of transcription factors and has been shown to play a critical role in maintaining the functions of CSCs and promoting tumor initiation. However, the underlying mechanisms for the transcriptional regulation of the SOX2 gene in CSCs are unclear. In this study, using in silico and experimental approaches, we identified transcriptional repressor GATA binding 1 (TRPS1), an atypical GATA-type transcription factor, as a critical transcriptional regulator that represses SOX2 expression and thereby suppresses cancer stemness and tumorigenesis. Mechanistically, TRPS1 repressed SOX2 expression by directly targeting the consensus GATA-binding element in the SOX2 promoter as elucidated by ChIP and luciferase reporter assays. Of note, in vitro mammosphere formation assays in culture and in vivo xenograft tumor initiation experiments in mouse models revealed that TRPS1-mediated repression of SOX2 expression suppresses CSC functions and tumor initiation. Taken together, our study provides detailed mechanistic insights into CSC functions and tumor initiation by the TRPS1-SOX2 axis.

Keywords: GATA-binding element; SOX2; TRPS1; breast cancer; cancer biology; cancer stem cells; cancer stemness; carcinogenesis; gene expression; transcription regulation; tumor initiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis*
  • Cell Line
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Silencing
  • Heterografts
  • Humans
  • Mice
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Promoter Regions, Genetic
  • Repressor Proteins
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • DNA-Binding Proteins
  • Repressor Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • TRPS1 protein, human
  • Transcription Factors
  • gamma-Aminobutyric Acid