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

Regulation of MYC expression and differential JQ1 sensitivity in cancer cells.

Author information

1
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
2
Biochemistry Department, University of Iowa, Iowa City, Iowa, United States of America.
3
Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
4
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
5
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
6
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, United States of America ; Program in Genetics, Sackler School of Biomedical Science, Tufts University School of Medicine, Boston, Massachusetts, United States of America ; Program in Immunology, Sackler School of Biomedical Science, Tufts University School of Medicine, Boston, Massachusetts, United States of America.

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.

PMID:
24466310
PMCID:
PMC3900694
DOI:
10.1371/journal.pone.0087003
[Indexed for MEDLINE]
Free PMC Article

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