Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene

Mol Cell Biol. 2019 Oct 28;39(22):e00248-19. doi: 10.1128/MCB.00248-19. Print 2019 Nov 15.

Abstract

The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by chromatin immunoprecipitation (CHIP). Here, we demonstrate by both a proximity ligation assay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that in vivo, Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use in vivo.

Keywords: DNA binding; Max; Myc; Omomyc; cotranslational; rRNA; transcription.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation / methods
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism
  • Female
  • Genes, myc*
  • HCT116 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Peptide Fragments / genetics*
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Proto-Oncogene Proteins c-myc / pharmacology
  • Recombinant Proteins / pharmacology
  • Transcription, Genetic
  • Transcriptional Activation

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • MAX protein, human
  • MYC protein, human
  • Peptide Fragments
  • Proto-Oncogene Proteins c-myc
  • Recombinant Proteins
  • omomyc protein
  • DNA