RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells

• Published in: Carcinogenesis (New York) 2014-12, Vol.35 (12), p.2807-2814
• Main Authors: Su, Jung-Chen, Chiang, Heng-Chieh, Tseng, Ping-Hui, Tai, Wei-Tien, Hsu, Cheng-Yi, Li, Yong-Shi, Huang, Jui-Wen, Ko, Ching-Huai, Lin, Mai-Wei, Chu, Pei-Yi, Liu, Chun-Yu, Chen, Kuen-Feng, Shiau, Chung-Wai
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Blotting, Western; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Chromatin Immunoprecipitation; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Flow Cytometry; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunoenzyme Techniques; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Luciferases - metabolism; Male; Mice; Mice, Nude; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Phenylurea Compounds - pharmacology; Promoter Regions, Genetic - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Pyrroles - pharmacology; Real-Time Polymerase Chain Reaction; Regulatory Factor X Transcription Factors; Regulatory Factor X1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Signal Transduction - drug effects; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgu210

Regulatory factor X-1 (RFX-1) is a transcription factor that has been linked to negative regulation of tumor progression; however, its biological function and signaling cascades are unknown. Here, we performed several studies to elucidate the roles of RFX-1 in the regulation of SHP-1 in hepatocellular carcinoma (HCC) cells. Overexpression of RFX-1 resulted in the activation of SHP-1 and repressed colony formation of HCC cells. In addition, by a mouse xenograft model, we demonstrated that RFX-1 overexpression also inhibited the tumor growth of HCC cells in vivo, suggesting that RFX-1 is of potential interest for small-molecule-targeted therapy. We also found that SC-2001, a bipyrrole molecule, induced apoptosis in HCC cells through activating RFX-1 expression. SC-2001 induced RFX-1 translocation from the cytosol to nucleus, bound to the SHP-1 promoter, and activated SHP-1 transcription. In a xenograft model, knockdown of RFX-1 reversed the antitumor effect of SC-2001. Notably, SC-2001 is much more potent than sorafenib, a clinically approved drug for HCC, in in vitro and in vivo assays. Our study confirmed that RFX-1 acts as a tumor suppressor in HCC and might be a new target for HCC therapy. The findings of this study also provide a new lead compound for targeted therapy via the activation of the RFX-1/SHP-1 pathway.