HEY2 acting as a co-repressor with smad3 and smad4 interferes with the response of TGF-beta in hepatocellular carcinoma

Am J Transl Res. 2019 Jul 15;11(7):4367-4381. eCollection 2019.


The HEY2 (hairy and enhancer of split-related with YRPW motif 2) is reported to play potential roles in tumorigenesis. However, the underlying mechanism in tumorigenesis is remain elusive. The present study aims to investigate the molecular mechanism of biological function of HEY2 in hepatocellular carcinoma (HCC). Dysfunction of the transforming growth factor-beta (TGF-β) pathway plays a critical role in HCC pathogenesis. Here, we identified HEY2 as a suppressor for TGF-β biological response. We demonstrated that HEY2 protein in tumor cytoplasm was up-regulated in HCC. Further, HEY2 overexpression inhibited TGF-β-induced growth arrest of HCC cells and inhibited TGF-β-induced downregulation of c-Myc, both in mRNA and in protein levels. While knockdown of HEY2, by small interfering RNA, was shown to enhance the TGF-β-mediated biological response of HCC cells. Moreover, HEY2 could form complexes with Smad3 and Smad4 and repress Smad3/Smad4 transcriptional activity. In conclusion, our findings indicate a novel role of HEY2 in mediating the TGF-β/Smad signaling pathway in HCC tumorigenesis.

Keywords: HEY2; Smad; TGF-β; cell growth; hepatocellular carcinoma (HCC).