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.
Highlights
Cancer stem cells (CSCs) have been reported in a variety of cancers
We report that transcriptional repressor GATA binding 1 (TRPS1) represses SRY-box 2 (SOX2) expression by directly targeting its promoter and suppressing CSC functions and tumor initiation
SOX2 plays an important role in CSC functions [18]
Summary
Silencing TRPS1 significantly increased the luciferase activity of the SOX2 promoter in MCF7 cells (Fig. 2C) These observations indicated that TRPS1 repressed transcriptional activity of SOX2 promoter by targeting its GATA-binding element. Highly purified CSCs (ALDHϩ/CD44ϩ/CD24Ϫ) from breast cancer patient-derived xenografts expressed higher SOX2 and lower TRPS1 compared with other types of breast cancer cells (Fig. S5) These results provided further evidence that TRPS1 might suppress CSC function by repressing SOX2 expression in vitro. Cells with silenced TRPS1 had a much greater ability and cells with additional silencing of SOX2 had a much smaller ability to form tumors as compared with controls (Fig. 4, A and B, and Table 1) These results suggested that TRPS1 inhibited CSC functions and suppressed breast tumor initiation by repressing SOX2. Our results have demonstrated that the decreased expression of TRPS1, as a tumor suppressor, promotes SOX2 expression and tumor initiation (Fig. S7), providing new mechanistic insights into the regulation of SOX2 expression and CSC functions
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