FMNL2 destabilises COMMD10 to activate NF-κB pathway in invasion and metastasis of colorectal cancer

Br J Cancer. 2017 Oct 10;117(8):1164-1175. doi: 10.1038/bjc.2017.260. Epub 2017 Aug 17.


Background: Diaphanous-related formins (DRFs), actin necleator, have been known to participate in the progression of cancer cells. We previously reported that FMNL2 (Formin-like2), a member of DRFs, was a positive regulator in colorectal cancer (CRC) metastasis, yet proteins and pathways required for the function of this pro-invasive DRFs remain to be identified.

Methods: The relationship between FMNL2 and COMMD10 was examined using Co-IP, GST pull-down, immunofluorescence and in vitro ubiquitination assay. The in vitro and in vivo function of COMMD10 in CRC was evaluated using CCK-8 proliferation assay, plate colony formation, cell cycle, apoptosis and animal models. The inhibition of NF-κB signalling by COMMD10 was detected using dual-luciferase reporter assay and western blotting. Co-IP, GST pull-down and nuclear protein extraction assay were performed to evaluate the effect on p65 by COMMD10. Real-time PCR and western blotting were performed to detect expressions of FMNL2, COMMD10 and p65 in paired tissues.

Results: FMNL2 targets COMMD10 for ubiquitin-mediated proteasome degradation in CRC cells. COMMD10 targets p65 NF-κB (nuclear factor-κB) subunit and reduces its nuclear translocation, thereby leading to the inactivation of NF-κB pathway and suppression of CRC invasion and metastasis. Inhibition of NF-κB signalling by COMMD10 is necessary for FMNL2-mediated CRC cell behaviours. Downregulation of COMMD10 predicts poor prognosis of CRC patients. The expressions of FMNL2, COMMD10 and p65 are highly linked in CRC tissues.

Conclusions: These data demonstrate that the FMNL2/COMMD10/p65 axis acts as a critical regulator in the maintenance of metastatic phenotypes and is strongly associated with negative clinical outcomes.

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Carcinoma / metabolism*
  • Carcinoma / secondary
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Fluorescent Antibody Technique
  • Formins
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Proteasome Endopeptidase Complex / metabolism
  • Proteins / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction
  • Transcription Factor RelA / metabolism*
  • Tumor Stem Cell Assay


  • COMMD10 protein, human
  • FMNL2 protein, human
  • Formins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Proteins
  • RELA protein, human
  • Transcription Factor RelA
  • Proteasome Endopeptidase Complex