Retracted: DNA methylation-mediated downregulation of PTPN3 attenuates to boost TGF-β signaling in osteosarcoma cells.

Abstract

The misregulation of transforming growth factor-β (TGF-β) signaling can cause tumorigenesis, but the activation and suppression of TGF-β signaling are complicated biological processes. We discovered a protein tyrosine phosphatase nonreceptor 3 (PTPN3)-dependent regulatory mechanism in uncancerous osteoblast cells that involved a stabilizing PTPN3 interaction with the TGF-β type I receptor (TGFBR1), which impaired TGFBR1 ubiquitination by the Smurf2 (Smad ubiquitination regulatory factor 2) E3 ligase. TGFBR1 facilitated the phosphorylation of Smad2/3 (SMAD family member 2 and 3), and the phosphorylated Smad2/3 recruited Smad4 to assemble a complex that then was translocated into the nucleus to initiate gene transcription. By contrast, PTPN3 was significantly downregulated in osteosarcoma cells because the increased DNMT1 (DNA methyltransferase 1) caused a higher methylation level in the promoter of PTPN3. The decrease of PTPN3 failed to stabilize TGFBR1, causing the ubiquitination and degradation of TGFBR1 by Smurf2. The degradation of TGFBR1 impaired the phosphorylation of Smad2/3 and prevented the nuclear translocation of the Smad2/3/4 complex, thereby causing the dysregulation of TGF-β target genes and triggering tumorigenesis. Collectively, our results reveal that the DNA methylation-mediated downregulation of PTPN3 disables the stabilization of TGFBR1 and that the degradation of TGFBR1 by Smurf2 E3 ligase blocks Smad2/3/4-mediated gene expression that promotes the tumorigenesis of osteosarcoma.