The LIM protein AJUBA promotes colorectal cancer cell survival through suppression of JAK1/STAT1/IFIT2 network

Oncogene. 2017 May 11;36(19):2655-2666. doi: 10.1038/onc.2016.418. Epub 2016 Nov 28.

Abstract

The LIM protein AJUBA is a scaffold protein participating in the regulation of cell adhesion, mitosis, DNA damage, cell differentiation, proliferation, migration and gene transcription. However, its roles in tumorigenesis and progression are poorly defined. Here, we report that AJUBA is highly expressed in colorectal cancer (CRC) and promotes CRC cell growth in culture and in xenografted mice via an inhibition of apoptosis. AJUBA represses the expression of IFIT2 gene, an interferon-stimulated gene and a known apoptosis inducer and tumour suppressor to mediate its resistance to apoptosis. Mechanistic investigations reveal that AJUBA specifically binds the FERM domain of JAK1 to dissociate JAK1 from the IFNγ recepter, resulting in an inhibition of STAT1 phosporylation and concomitantly its nuclear translocation. Clinically, the level of AJUBA in CRC specimens is negatively correlated with the levels of IFIT2 and pSTAT1. Collectively, these studies demonstrate that AJUBA can promote CRC growth via inhibiting apoptosis and serve as a target for the therapeutics and a marker for diagnosis of CRC.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins
  • Carcinogenesis / genetics
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferon-gamma / genetics
  • Janus Kinase 1 / genetics*
  • LIM Domain Proteins / genetics*
  • Mice
  • Proteins / genetics*
  • RNA-Binding Proteins
  • STAT1 Transcription Factor / genetics*
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Substances

  • AJUBA protein, human
  • Apoptosis Regulatory Proteins
  • IFIT2 protein, human
  • LIM Domain Proteins
  • Proteins
  • RNA-Binding Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Interferon-gamma
  • JAK1 protein, human
  • Janus Kinase 1