Iroquois-homeobox protein 3 promotes hepatocellular carcinoma growth by transcriptionally upregulating F2R like trypsin receptor 1/protease-activated receptor 2.

Dimethyl sulfoxide can be used to promote mature hepatocyte-like differentiation in hepatocellular carcinoma cells and sustain the expression of liver-specific genes, which is considered a potential novel therapy for liver cancer treatment. However, the molecular targets of dimethyl sulfoxide, especially transcription factors, remain largely unknown. In this study, we show that dimethyl sulfoxide treatment significantly downregulates Iroquois-homeobox protein 3 in Hepatocellular carcinoma cells, illustrating that Iroquois-homeobox protein 3 might regulate Hepatocellular carcinoma proliferation positively. Further clinical data reveal that Iroquois-homeobox protein 3 expression is generally elevated in human Hepatocellular carcinoma tissues and correlates with poor patient survival. Consistent with these observations, gain- and loss-of-function studies demonstrate that Iroquois-homeobox protein 3 promotes Hepatocellular carcinoma proliferation both in vitro and in vivo. Mechanistically, Iroquois-homeobox protein 3 binds to the promoter of F2R-like trypsin receptor 1/Protease-Activated Receptor 2, recruits RNA polymerase II and increases Serine 5 phosphorylation of its C-terminal domain (CTD), thereby upregulating F2R-like trypsin receptor 1/Protease-Activated Receptor 2 expression and driving Hepatocellular carcinoma proliferation. Collectively, our findings reveal a critical role for Iroquois-homeobox protein 3 in Hepatocellular carcinoma development and suggest that Iroquois-homeobox protein 3 might be a potential therapeutic target for Hepatocellular carcinoma.