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

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 <i>SOX2</i> gene in CSCs are unclear. In this study, using <i>in silico</i> and experimental approaches, we identified transcriptional repressor GATA binding 1 (TRPS1), an atypical GATA-type transcription factor, as a critical transcriptional regulator that represses <i>SOX2</i> expression and thereby suppresses cancer stemness and tumorigenesis. Mechanistically, TRPS1 repressed <i>SOX2</i> expression by directly targeting the consensus GATA-binding element in the <i>SOX2</i> promoter as elucidated by ChIP and luciferase reporter assays. Of note, <i>in vitro</i> mammosphere formation assays in culture and <i>in vivo</i> 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.