XAF1 promotes colorectal cancer metastasis via VCP-RNF114-JUP axis

J Cell Biol. 2024 Feb 5;223(2):e202303015. doi: 10.1083/jcb.202303015. Epub 2023 Dec 14.


Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1-VCP-RNF114-JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1-VCP-RNF114-JUP axis is a potential therapeutic target for CRC treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing* / metabolism
  • Apoptosis
  • Apoptosis Regulatory Proteins* / metabolism
  • Colorectal Neoplasms* / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Neoplasm Proteins / metabolism
  • Valosin Containing Protein / genetics
  • Valosin Containing Protein / metabolism
  • gamma Catenin / metabolism


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • gamma Catenin
  • Intracellular Signaling Peptides and Proteins
  • JUP protein, human
  • Neoplasm Proteins
  • Valosin Containing Protein
  • VCP protein, human
  • XAF1 protein, human