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

G. Zurlo, X. Liu, M. Takada, C. Fan, JM. Simon, TS. Ptacek, J. Rodriguez, A. von Kriegsheim, J. Liu, JW. Locasale, A. Robinson, J. Zhang, JM. Holler, B. Kim, M. Zikánová, J. Bierau, L. Xie, X. Chen, M. Li, CM. Perou, Q. Zhang,

. 2019 ; 10 (1) : 5177. [pub] 20191115

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20005697

Grantová podpora
P30 ES010126 NIEHS NIH HHS - United States
P30 NS045892 NINDS NIH HHS - United States
R01 AI136581 NIAID NIH HHS - United States
U54 HD079124 NICHD NIH HHS - United States
Wellcome Trust - United Kingdom
R00 CA160351 NCI NIH HHS - United States
R21 CA223675 NCI NIH HHS - United States
R01 CA211732 NCI NIH HHS - United States

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.

Cancer Research UK Edinburgh Centre IGMM University of Edinburgh Edinburgh EH4 2XR UK

Department of Biochemistry and Biophysics University of North Carolina Chapel Hill NC 27599 USA

Department of Clinical Genetics Maastricht University Medical Centre Maastricht The Netherlands

Department of Pediatrics School of Medicine Emory University Atlanta GA 30322 USA

Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham NC 27710 USA

Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine Chapel Hill NC 27599 USA

Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine Chapel Hill NC 27599 USA Department of Genetics Neuroscience Center University of North Carolina Chapel Hill NC 27599 USA UNC Neuroscience Center Carolina Institute for Developmental Disabilities University of North Carolina Chapel Hill NC 27599 USA

Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine Chapel Hill NC 27599 USA Department of Pathology and Laboratory Medicine University of North Carolina Chapel Hill NC 27599 USA

Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine Chapel Hill NC 27599 USA Department of Pathology and Laboratory Medicine University of North Carolina Chapel Hill NC 27599 USA Department of Pharmacology University of North Carolina Chapel Hill NC 27599 USA Department of Pathology UT Southwestern Medical Center Dallas TX 75390 USA

Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine Chapel Hill NC 27599 USA UNC Neuroscience Center Carolina Institute for Developmental Disabilities University of North Carolina Chapel Hill NC 27599 USA

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Citace poskytuje Crossref.org

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