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

Carcinogenesis. 2014 Dec;35(12):2807-14. doi: 10.1093/carcin/bgu210. Epub 2014 Oct 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Sorafenib
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • 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