Proteasome inhibitors suppress MYB oncogenic activity in a p300-dependent manner

Cancer Lett. 2021 Nov 1:520:132-142. doi: 10.1016/j.canlet.2021.07.010. Epub 2021 Jul 10.

Abstract

Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often considered un-druggable, recent work has demonstrated successful targeting of MYB by low molecular weight compounds. This has fueled the notion that inhibition of MYB has potential as a therapeutic approach against MYB-driven malignancies. Here, we have used a MYB reporter cell line to screen a library of FDA-approved drugs for novel MYB inhibitors. We demonstrate that proteasome inhibitors have significant MYB-inhibitory activity, prompting us to characterize the proteasome inhibitor oprozomib in more detail. Oprozomib was shown to interfere with the ability of the co-activator p300 to stimulate MYB activity and to exert anti-proliferative effects on human AML and ACC cells. Overall, our work demonstrated suppression of oncogenic MYB activity as a novel result of proteasome inhibition.

Keywords: Adenoid cystic carcinoma; Inhibitor; MYB; Myeloid leukemia; Proteasome inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Adenoid Cystic / drug therapy*
  • Carcinoma, Adenoid Cystic / genetics
  • Carcinoma, Adenoid Cystic / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • E1A-Associated p300 Protein / genetics*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Molecular Targeted Therapy
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-myb / genetics*

Substances

  • MYB protein, human
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-myb
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Proteasome Endopeptidase Complex