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

Abstract

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.

• Authors: Jung-Chen Su, Heng-Chieh Chiang, Ping-Hui Tseng, Wei-Tien Tai, Cheng-Yi Hsu, Yong-Shi Li, Jui-Wen Huang, Ching-Huai Ko, Mai-Wei Lin, Pei-Yi Chu, Chun-Yu Liu, Kuen-Feng Chen, Chung-Wai Shiau
• Journal: Carcinogenesis (Carcinogenesis) Vol. 35 Issue 12 Pg. 2807-14 (Dec 2014) ISSN: 1460-2180 [Electronic] England
• PMID: 25322871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• Phenylurea Compounds
• Pyrroles
• RFX1 protein, human
• RNA, Messenger
• RNA, Small Interfering
• Regulatory Factor X Transcription Factors
• Regulatory Factor X1
• Rfx1 protein, mouse
• SC-2001
• STAT3 Transcription Factor
• STAT3 protein, human
• Transcription Factors
• Niacinamide
• Sorafenib
• Luciferases
• PTPN6 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 6

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism, pathology)
• Chromatin Immunoprecipitation
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunoenzyme Techniques
• Liver Neoplasms (drug therapy, genetics, metabolism, pathology)
• Luciferases (metabolism)
• Male
• Mice
• Mice, Nude
• Niacinamide (analogs & derivatives, pharmacology)
• Phenylurea Compounds (pharmacology)
• Promoter Regions, Genetic (genetics)
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (genetics, metabolism)
• Pyrroles (pharmacology)
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Regulatory Factor X Transcription Factors
• Regulatory Factor X1
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Sorafenib
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays