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Crotonylation impedes c-Myc oncogenic activity

Nicholas J Wallbillich1,2, Peng Liao1,2, Rashmi Srivastava1,2

  • 1Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112.

Proceedings of the National Academy of Sciences of the United States of America
|June 1, 2026
PubMed

Insights

Crotonylation, a modification of the oncoprotein c-Myc, impairs its cancer-driving activity. Specific mutations in c-Myc enhance its oncogenic functions by altering interactions with its regulator Skp2.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • c-Myc is a crucial oncoprotein regulated by posttranslational modifications.
  • Understanding these modifications is key to comprehending c-Myc's role in cancer.

Purpose of the Study:

  • To investigate c-Myc crotonylation, a novel posttranslational modification.
  • To determine the functional impact of c-Myc crotonylation on its oncogenic activity.

Main Methods:

  • Biochemical analyses and high-resolution mass spectrometry were employed.
  • Site-directed mutagenesis of identified crotonylation sites was performed.
  • Interactions between c-Myc and Skp2 were assessed.

Main Results:

  • c-Myc was found to be crotonylated at multiple lysine residues.
  • Mutations at K289 and K298 enhanced cell proliferation and c-Myc binding to Skp2.
  • The K298N mutation, found in human tumors, exhibited increased oncogenic activity.
  • Crotonylation impairs c-Myc's oncogenic activity by modulating Skp2 interaction.

Conclusions:

  • Crotonylation is a regulatory mechanism for c-Myc.
  • This modification can attenuate c-Myc's oncogenic potential.
  • Targeting c-Myc crotonylation may offer therapeutic strategies in cancer treatment.
Keywords:
Skp2c-Myccrotonylationoncogenesisposttranslational modification

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