MEK-mediated CHPF2 phosphorylation promotes colorectal cancer cell proliferation and metastasis by activating NF-κB signaling

Cancer Lett. 2024 Mar 1:584:216644. doi: 10.1016/j.canlet.2024.216644. Epub 2024 Jan 21.


The cytokine tumor necrosis factor (TNF) plays a crucial role in the proliferation and metastasis of colorectal cancer (CRC) cells, but the underlying mechanisms remain poorly understood. Here, we report that chondroitin polymerizing factor 2 (CHPF2) promotes CRC cell proliferation and metastasis mediated by TNF, independently of its enzymatic activity. CHPF2 is highly expressed in CRC, and its elevated expression is associated with poor prognosis of CRC patients. Mechanistically, upon TNF stimulation, CHPF2 is phosphorylated at the T588 residue by MEK, enabling CHPF2 to interact with both TAK1 and IKKα. This interaction enhances the binding of TAK1 and IKKα, leading to increased phosphorylation of the IKK complex and activation of NF-κB signaling. As a result, the expression of early growth factors (EGR1) is upregulated to promote CRC cell proliferation and metastasis. In contrast, introduction of a phospho-deficient T588A mutation in CHPF2 weakened the interaction between CHPF2 and TAK1, thus impairing NF-κB signaling. CHPF2 T588A mutation reduced the ability of CHPF2 to promote the proliferation and metastasis of CRC in vitro and in vivo. Furthermore, the NF-κB RELA subunit promotes CHPF2 expression, further amplifying TNF-induced NF-κB signaling activation. These findings identify a moonlighting function of CHPF2 in promoting tumor cell proliferation and metastasis and provide insights into the mechanism by which CHPF2 amplifies TNF-mediated NF-κB signaling activation. Our study provides a molecular basic for the development of therapeutic strategies for CRC treatment.

Keywords: CHPF2 phosphorylation; Colorectal cancer proliferation and metastasis; MEK kinase; NF-κB signaling; TNF.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms* / pathology
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NF-kappa B* / metabolism
  • Phosphorylation
  • Tumor Necrosis Factor-alpha / metabolism


  • NF-kappa B
  • I-kappa B Kinase
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinase Kinases