Regulation of MYC expression and differential JQ1 sensitivity in cancer cells

PLoS One. 2014 Jan 23;9(1):e87003. doi: 10.1371/journal.pone.0087003. eCollection 2014.

Abstract

High level MYC expression is associated with almost all human cancers. JQ1, a chemical compound that inhibits MYC expression is therapeutically effective in preclinical animal models in midline carcinoma, and Burkitt's lymphoma (BL). Here we show that JQ1 does not inhibit MYC expression to a similar extent in all tumor cells. The BL cells showed a ∼90% decrease in MYC transcription upon treatment with JQ1, however, no corresponding reduction was seen in several non-BL cells. Molecularly, these differences appear due to requirements of Brd4, the most active version of the Positive Transcription Elongation Factor B (P-TEFb) within the Super Elongation Complex (SEC), and transcription factors such as Gdown1, and MED26 and also other unknown cell specific factors. Our study demonstrates that the regulation of high levels of MYC expression in different cancer cells is driven by unique regulatory mechanisms and that such exclusive regulatory signatures in each cancer cells could be employed for targeted therapeutics.

Publication types

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

MeSH terms

  • Azepines / pharmacology*
  • Blotting, Western
  • Burkitt Lymphoma / drug therapy*
  • Burkitt Lymphoma / metabolism
  • Burkitt Lymphoma / pathology
  • Cell Cycle Proteins
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Mediator Complex / genetics
  • Mediator Complex / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Triazoles / pharmacology*
  • Tumor Cells, Cultured

Substances

  • (+)-JQ1 compound
  • Azepines
  • BRD4 protein, human
  • Cell Cycle Proteins
  • MED26 protein, human
  • MYC protein, human
  • Mediator Complex
  • Nuclear Proteins
  • POLR2M protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Transcription Factors
  • Triazoles
  • RNA Polymerase II