title: The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy.
abstract: Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Here we report that the transcription factor c-Jun, product of the proto-oncogene JUN, is a key regulator of mitochondrial glutaminase (GLS) levels. Activation of c-Jun downstream of oncogenic Rho GTPase signalling leads to elevated GLS gene expression and glutaminase activity. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition correlate strongly with c-Jun levels. We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression. Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity. These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lukey
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Kai Su
authors.initials: KS
authors.lastname: Greene
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Erickson
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Kristin F
authors.initials: KF
authors.lastname: Wilson
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.|Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005972:Glutaminase / Q000235:genetics* / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D005973:Glutamine; D005972:Glutaminase; D020741:rho GTP-Binding Proteins