Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer
Year: 2019
Type: article
Abstract: Protein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.
Source: Nature Communications
Authors: Giada Zurlo, Xijuan Liu, Mamoru Takada, Cheng Fan, Jeremy M. Simon, Travis S. Ptacek, Javier Rodriguez, Alex von Kriegsheim, Juan Liu, Jason W. Locasale, Adam Robinson, Jing Zhang, Jessica M. Holler, Baek Kim, Marie Zikánová, Jörgen Bierau, Ling Xie, Xian Chen, Mingjie Li, Charles M. Perou, Qing Zhang
Institutions: University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, Edinburgh Cancer Research, Institute of Genetics and Cancer, University of Edinburgh, Duke University, Emory University, Charles University, General University Hospital in Prague, Maastricht University Medical Centre, The University of Texas Southwestern Medical Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Health and Human Services, Mary Kay Foundation, V Foundation for Cancer Research, Cancer Prevention and Research Institute of Texas, Univerzita Karlova v Praze, Wellcome Trust, Ministerstvo Školství, Mládeže a Tělovýchovy, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1017297203, G1540680213, G1957650369, G1989292043, G201185739, G2372839465, G2390358516, G339059223, High resolution metabolite and peptide mass spectrometry, G4013523069, G4482901214, G4667312900, High resolution metabolite and peptide mass spectrometry, G506752177, G527544857, G5915502376, G6191335359, G6284389483, Exploration of ZHX2 as a novel substrate of pVHL and an oncogenic driver of renal cancer, G7667060700, BIOCEV: from Fundamental to Applied Research, G888696657, G9000031743, G9000118262, G9000185219, G9000291434, Lentivirus Replication Strategy and Pathogenesis, UNC Center for Environmental Health and Susceptibility, G960855989
OpenAlex ID: W2987204574