Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3.
Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1-3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition in vitro and in vivo. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. CRISPR/Cas9-mediated EIF4EBP3 gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer.
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Cancer Pavilion 1160 Pine Avenue West, Montreal, Quebec, Canada H3A 1A3.
Yoshinori
Y
Tsukumo
Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8L1.
Tommy
T
Alain
Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8L1.
Bruno D
BD
Fonseca
McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1A5.
Robert
R
Nadon
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Cancer Pavilion 1160 Pine Avenue West, Montreal, Quebec, Canada H3A 1A3.
Nahum
N
Sonenberg
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D064113:CRISPR-Cas Systems; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D030541:Databases, Genetic; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000072669:Gene Editing / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C104151:EIF4EBP2 protein, human; C112661:EIF4EBP3 protein, human; D039642:Eukaryotic Initiation Factors; D007211:Indoles; D010750:Phosphoproteins; D011687:Purines; C069203:TFE3 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus