@article{6469e977782447c38cb857c2a04b6542,
title = "Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer",
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 EgIN2 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 noncoding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.",
keywords = "PROLINE-HYDROXYLATION, MASS-SPECTROMETRY, MESSENGER-RNA, HIF-ALPHA, PURINE, MYC, IDENTIFICATION, TUMORIGENESIS, METABOLISM, MIR22HG",
author = "Giada Zurlo and Xijuan Liu and Mamoru Takada and Cheng Fan and Simon, {Jeremy M.} and Ptacek, {Travis S.} and Javier Rodriguez and {von Kriegsheim}, Alex and Juan Liu and Locasale, {Jason W.} and Adam Robinson and Jing Zhang and Holler, {Jessica M.} and Baek Kim and Marie Zikanova and Jorgen Bierau and Ling Xie and Xian Chen and Mingjie Li and Perou, {Charles M.} and Qing Zhang",
note = "Funding Information: We thank all members of the Zhang and Perou laboratories for helpful discussions and suggestions; Dong-Yan Zhang and De-Hua Wu for providing MIR22HG overexpression plasmid; UNC Proteomics Center (particularly Laura Herring), UNC Tissue Procurement Facility, and UNC Animal Studies Core. Q.Z. was supported by The V Foundation Scholar Award, University Cancer Research Fund, Mary Kay Foundation, National Cancer Institute (Q.Z., R01CA211732, R21CA223675), Kimmel Scholar Award, and Susan G. Komen Career Catalyst Award. A.v.K. was supported by Wellcome Trust (Multiuser Equipment Grant, 208402/Z/17/Z). J.M.S. and T.S.P. were supported by The Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079124) and NINDS (P30NS045892). J.M.H. and B.K. were supported by NIH (R01AI136581). M.Z. was supported by Charles University [programmes PRIMUS/17/ MED/6 and PROGRES Q26/LF1] and by the Ministry of Education, Youth and Sports of CR [LQ1604 National Sustainability Programme II]. This work was also supported in part by Cancer Prevention and Research Institute of Texas (CPRIT, RP190058 to Q.Z.). Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = nov,
day = "15",
doi = "10.1038/s41467-019-13168-4",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}