USF2 inhibits the transcriptional activity of Smurf1 and Smurf2 to promote breast cancer tumorigenesis

Smurf1 (Smad ubiquitylation regulatory factor 1) and Smurf2 are negative regulators of the TGF-β (transforming growth factor-β) pathway. The protein stability and ubiquitin E3 activity regulation of Smurfs have been well studied. However, the mechanism of Smurfs expression at the transcriptional level remains uncharacterized. Here, we reported that USF2 (upstream stimulatory factor 2), a basic helix-loop-helix-leucine-zip transcription factor, is necessary for the transcriptional activity of Smurf1 and Smurf2. The 5′-flanking sequences of the Smurfs gene have more than one E-box motifs, and USF2 bounds the Smurfs promoter in vitro and in vivo. Over-expression USF2 inhibited the transcriptional activity of the Smurfs, and Smurfs mRNA was markedly decreased. Therefore, the activity of TGF-β was distinctly enhanced. Furthermore, in human breast cancers, USF2 was abnormally high expressed and correlated with cancer progression. USF2 was specifically inversely correlated with Smurfs in Luminal A subtype breast cancer patients. These findings suggest the mechanism regulation of Smurfs transcriptional activity, and shed new light on the cancer-promoting role of USF2.