Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

Giada Zurlo, Xijuan Liu, Mamoru Takada, Cheng Fan, Jeremy M. Simon, Travis S. Ptacek, Javier Rodriguez, Alex 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 and Qing Zhang ()
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Giada Zurlo: University of North Carolina School of Medicine
Xijuan Liu: University of North Carolina School of Medicine
Mamoru Takada: University of North Carolina School of Medicine
Cheng Fan: University of North Carolina School of Medicine
Jeremy M. Simon: University of North Carolina School of Medicine
Travis S. Ptacek: University of North Carolina School of Medicine
Javier Rodriguez: University of Edinburgh
Alex Kriegsheim: University of Edinburgh
Juan Liu: Duke University School of Medicine
Jason W. Locasale: Duke University School of Medicine
Adam Robinson: University of North Carolina School of Medicine
Jing Zhang: University of North Carolina School of Medicine
Jessica M. Holler: Emory University
Baek Kim: Emory University
Marie Zikánová: Charles University and General University Hospital in Prague
Jörgen Bierau: Maastricht University Medical Centre
Ling Xie: University of North Carolina
Xian Chen: University of North Carolina
Mingjie Li: University of North Carolina School of Medicine
Charles M. Perou: University of North Carolina School of Medicine
Qing Zhang: University of North Carolina School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13168-4

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