c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4

Cell Cycle. 2015;14(12):1859-72. doi: 10.1080/15384101.2015.1040965.


c-Myc is the most frequently overexpressed oncogene in tumors, including breast cancer, colon cancer and lung cancer. Post-translational modifications comprising phosphorylation, acetylation and ubiquitylation regulate the activity of c-Myc. Recently, it was shown that c-Myc-driven tumors are strongly dependent on the SUMO pathway. Currently, the relevant SUMO target proteins in this pathway are unknown. Here we show that c-Myc is a target protein for SUMOylation, and that SUMOylated c-Myc is subsequently ubiquitylated and degraded by the proteasome. SUMO chains appeared to be dispensable for this process, polymerization-deficient SUMO mutants supported proteolysis of SUMOylated c-Myc. These results indicate that multiple SUMO monomers conjugated to c-Myc could be sufficient to direct SUMOylated c-Myc to the ubiquitin-proteasome pathway. Knocking down the SUMO-targeted ubiquitin ligase RNF4 enhanced the levels of SUMOylated c-Myc, indicating that RNF4 could recognize a multi-SUMOylated protein as a substrate in addition to poly-SUMOylated proteins. Knocking down the SUMO E3 ligase PIAS1 resulted in reduced c-Myc SUMOylation and increased c-Myc transcriptional activity, indicating that PIAS1 mediates c-Myc SUMOylation. Increased SUMOylation of c-Myc was noted upon knockdown of the SUMO protease SENP7, indicating that it also could regulate a multi-SUMOylated protein in addition to poly-SUMOylated proteins. C-Myc lacks KxE-type SUMOylation consensus motifs. We used mass spectrometry to identify 10 SUMO acceptor lysines: K52, K148, K157, K317, K323, K326, K389, K392, K398 and K430. Intriguingly, mutating all 10 SUMO acceptor lysines did not reduce c-Myc SUMOylation, suggesting that SUMO acceptor lysines in c-Myc act promiscuously. Our results provide novel insight into the complexity of c-Myc post-translational regulation.

Keywords: PIAS1; RNF4; SENP7; SUMO; c-Myc; proteasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Endopeptidases / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Humans
  • Lysine / chemistry
  • Mass Spectrometry
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Inhibitors of Activated STAT / metabolism*
  • Protein Processing, Post-Translational
  • Protein Transport / genetics
  • Proteolysis
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Sumoylation
  • Transcription Factors / metabolism*
  • Ubiquitination


  • MYC protein, human
  • Nuclear Proteins
  • PIAS1 protein, human
  • Protein Inhibitors of Activated STAT
  • Proto-Oncogene Proteins c-myc
  • RNF4 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Transcription Factors
  • Endopeptidases
  • SENP7 protein, human
  • Proteasome Endopeptidase Complex
  • Lysine