PXD015773

PXD015773 is an original dataset announced via ProteomeXchange.

Title	Prolyl Hydroxylase Substrate Adenylosuccinate Lyase Is An Oncogenic Driver In Triple Negative Breast Cancer
Description	Protein hydroxylation extensively regulates cellular signaling by affecting protein stability, protein-protein interaction and protein activity, and its dysregulation contributes to the pathogenesis of various diseases including cancers. However, because of the transient nature of the enzyme-substrate interaction, identifying new prolyl hydroxylation substrates remains a daunting challenge. Here, by developing a novel substrate-trapping strategy combining tumor hypoxia and hydroxylase pharmacological inhibition with TAP-TAG purification followed by mass spectrometry, we identify ADSL as a bona fide EglN2 prolyl hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is significantly higher in TNBC than in the other breast cancer subtypes and normal breast tissues. Functionally, ADSL knock out greatly impairs TNBC 2-D and 3-D cell proliferation and invasiveness in vitro, as well as TNBC tumorigenesis and metastasis in xenograft models. Mechanistically, the integrated transcriptome and metabolome analysis reveals that ADSL promotes the activation of the oncogene cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL hydroxylation. Specifically, ADSL, by affecting adenosine levels, controls the expression of the long non-coding RNA MIR22HG, which negatively regulates the oncogene cMYC protein level and, thus, cMYC target gene expression. Our findings identify ADSL and ADSL hydroxylation as potential therapeutic targets in TNBC.
HostingRepository	PRIDE
AnnounceDate	2019-11-27
AnnouncementXML	Submission_2019-11-27_06:51:45.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex von kriegsheim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-10-10 03:14:19	ID requested
1	2019-11-19 18:58:13	announced
⏵ 2	2019-11-27 06:51:47	announced	2019-11-27: Updated project metadata.

Zurlo G, Liu X, Takada M, Fan C, Simon JM, Ptacek TS, Rodriguez J, von Kriegsheim A, Liu J, Locasale JW, Robinson A, Zhang J, Holler JM, Kim B, Zik, á, nov, á M, Bierau J, Xie L, Chen X, Li M, Perou CM, Zhang Q, Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer. Nat Commun, 10(1):5177(2019) [pubmed]

submitter keyword: breast cancer, hydroxylation, PTM

Qing Zhang
contact affiliation	Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine,Chapel Hill, NC 27599, USA
contact email	Qing.Zhang@UTSouthwestern.edu
lab head
Alex von kriegsheim
contact affiliation	Systems Biology
contact email	alex.vonkriegsheim@ucd.ie
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015773
     1. Label: PRIDE project
     2. Name: Prolyl Hydroxylase Substrate Adenylosuccinate Lyase Is An Oncogenic Driver In Triple Negative Breast Cancer