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 von Kriegsheim, Juan Liu, Jason W. Locasale, Adam Robinson, Jing Zhang, Jessica M. Holler, Baek Kim, Marie Zikanova, Jorgen Bierau, Ling Xie, Xian Chen, Mingjie Li, Charles M. PerouQing Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)

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.

Original languageEnglish
Article number5177
Number of pages15
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 15 Nov 2019

Keywords

  • PROLINE-HYDROXYLATION
  • MASS-SPECTROMETRY
  • MESSENGER-RNA
  • HIF-ALPHA
  • PURINE
  • MYC
  • IDENTIFICATION
  • TUMORIGENESIS
  • METABOLISM
  • MIR22HG

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