MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation

Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5481-90. doi: 10.1073/pnas.1610994113. Epub 2016 Aug 26.

Abstract

MYC-nick is a cytoplasmic, transcriptionally inactive member of the MYC oncoprotein family, generated by a proteolytic cleavage of full-length MYC. MYC-nick promotes migration and survival of cells in response to chemotherapeutic agents or withdrawal of glucose. Here we report that MYC-nick is abundant in colonic and intestinal tumors derived from mouse models with mutations in the Wnt, TGF-β, and PI3K pathways. Moreover, MYC-nick is elevated in colon cancer cells deleted for FBWX7, which encodes the major E3 ligase of full-length MYC frequently mutated in colorectal cancers. MYC-nick promotes the migration of colon cancer cells assayed in 3D cultures or grown as xenografts in a zebrafish metastasis model. MYC-nick accelerates migration by activating the Rho GTPase Cdc42 and inducing fascin expression. MYC-nick, fascin, and Cdc42 are frequently up-regulated in cells present at the invasive front of human colorectal tumors, suggesting a coordinated role for these proteins in tumor migration.

Keywords: MYC; MYC-nick; colon cancer; fascin; motility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Microfilament Proteins / genetics*
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins c-myc / genetics*
  • Signal Transduction
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Transcriptional Activation / genetics
  • Zebrafish
  • cdc42 GTP-Binding Protein / genetics*

Substances

  • Carrier Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MYC protein, human
  • Microfilament Proteins
  • Proto-Oncogene Proteins c-myc
  • fascin
  • cdc42 GTP-Binding Protein