Regulation of MYC expression and differential JQ1 sensitivity in cancer cells.
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.
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Trent
T
Fowler
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Payel
P
Ghatak
Biochemistry Department, University of Iowa, Iowa City, Iowa, United States of America.
David H
DH
Price
Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
Ronald
R
Conaway
Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
Joan
J
Conaway
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Cheng-Ming
CM
Chiang
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
James E
JE
Bradner
Stowers Institute for Medical Research, Kansas City, Missouri, United States of America.
Ali
A
Shilatifard
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.
Ananda L
AL
Roy
D001381:Azepines / Q000494:pharmacology*; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D018797:Cell Cycle Proteins; D056892:Mediator Complex; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012319:RNA Polymerase II; D012333:RNA, Messenger; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C492155:MED26 protein, human; C489427:MYC protein, human; C433812:POLR2M protein, human