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The transcription factors aryl hydrocarbon receptor and MYC cooperate in the regulation of cellular metabolism.
J Biol Chem. 2020 Jul 01 [Online ahead of print]JB

Abstract

The transcription factor aryl hydrocarbon receptor (AHR) drives the expression of genes involved in detoxification pathways in cells exposed to pollutants and other small molecules. Moreover, AHR supports transcriptional programs that promote ribosome biogenesis and protein synthesis in cells stimulated to proliferate by the oncoprotein MYC. Thus, AHR is necessary for the proliferation of MYC-overexpressing cells. To define metabolic pathways in which AHR cooperates with MYC in supporting cell growth, here we used LC-MS-based metabolomics to examine the metabolome of MYC-expressing cells uponAHR knockdown. We found that AHR knockdown reduced lactate, S-lactoyl-glutathione,N-acetyl-L-alanine, 2-hydroxyglutarate, and uridine-5-monophosphate (UMP) levels. Using our previously obtained RNA-seq data, we found that AHR mediates the expression of the UMP-generating enzymes dihydroorotate dehydrogenase (quinone) (DHODH) and uridine monophosphate synthetase (UMPS), as well as lactate dehydrogenase A (LDHA), establishing a mechanism by which AHR regulates lactate and UMP production in MYC-overexpressing cells. AHR knockdown in glioblastoma cells also reduced the expression of LDHA (and lactate), DHODH,and UMPS, but did not affect UMP levels, likely due to compensatory mechanisms in these cells. Our results indicate that AHR contributes to the regulation of metabolic pathways necessary for the proliferation of transformed cells.

Authors+Show Affiliations

Department of Cell Biology, UT Southwestern Medical Center, United States.UT Southwestern Medical Center, United States.UT Southwestern Medical Center, United States.UT Southwestern Medical Center, United States.UT Southwestern Medical Center, United States.Cell Biology, UT Southwestern Medical Center, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32611766

Citation

Lafita-Navarro, M Carmen, et al. "The Transcription Factors Aryl Hydrocarbon Receptor and MYC Cooperate in the Regulation of Cellular Metabolism." The Journal of Biological Chemistry, 2020.
Lafita-Navarro MC, Perez-Castro L, Zacharias LG, et al. The transcription factors aryl hydrocarbon receptor and MYC cooperate in the regulation of cellular metabolism. J Biol Chem. 2020.
Lafita-Navarro, M. C., Perez-Castro, L., Zacharias, L. G., Barnes, S., DeBerardinis, R. J., & Conacci-Sorrell, M. (2020). The transcription factors aryl hydrocarbon receptor and MYC cooperate in the regulation of cellular metabolism. The Journal of Biological Chemistry. https://doi.org/10.1074/jbc.AC120.014189
Lafita-Navarro MC, et al. The Transcription Factors Aryl Hydrocarbon Receptor and MYC Cooperate in the Regulation of Cellular Metabolism. J Biol Chem. 2020 Jul 1; PubMed PMID: 32611766.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The transcription factors aryl hydrocarbon receptor and MYC cooperate in the regulation of cellular metabolism. AU - Lafita-Navarro,M Carmen, AU - Perez-Castro,Lizbeth, AU - Zacharias,Lauren G, AU - Barnes,Spencer, AU - DeBerardinis,Ralph J, AU - Conacci-Sorrell,Maralice, Y1 - 2020/07/01/ PY - 2020/07/01/accepted PY - 2020/05/02/received PY - 2020/7/3/entrez KW - Myc (c-Myc) KW - aryl hydrocarbon receptor (AhR) (AHR) KW - cancer KW - gene regulation KW - glioblastoma KW - glycolysis KW - metabolism KW - metabolomics KW - oncogene KW - pyrimidine JF - The Journal of biological chemistry JO - J. Biol. Chem. N2 - The transcription factor aryl hydrocarbon receptor (AHR) drives the expression of genes involved in detoxification pathways in cells exposed to pollutants and other small molecules. Moreover, AHR supports transcriptional programs that promote ribosome biogenesis and protein synthesis in cells stimulated to proliferate by the oncoprotein MYC. Thus, AHR is necessary for the proliferation of MYC-overexpressing cells. To define metabolic pathways in which AHR cooperates with MYC in supporting cell growth, here we used LC-MS-based metabolomics to examine the metabolome of MYC-expressing cells uponAHR knockdown. We found that AHR knockdown reduced lactate, S-lactoyl-glutathione,N-acetyl-L-alanine, 2-hydroxyglutarate, and uridine-5-monophosphate (UMP) levels. Using our previously obtained RNA-seq data, we found that AHR mediates the expression of the UMP-generating enzymes dihydroorotate dehydrogenase (quinone) (DHODH) and uridine monophosphate synthetase (UMPS), as well as lactate dehydrogenase A (LDHA), establishing a mechanism by which AHR regulates lactate and UMP production in MYC-overexpressing cells. AHR knockdown in glioblastoma cells also reduced the expression of LDHA (and lactate), DHODH,and UMPS, but did not affect UMP levels, likely due to compensatory mechanisms in these cells. Our results indicate that AHR contributes to the regulation of metabolic pathways necessary for the proliferation of transformed cells. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/32611766/The_transcription_factors_aryl_hydrocarbon_receptor_and_MYC_cooperate in_the_regulation_of_cellular_metabolism L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=32611766 DB - PRIME DP - Unbound Medicine ER -
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