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http://purl.uniprot.org/citations/29615789http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/29615789http://www.w3.org/2000/01/rdf-schema#comment"Alterations in both cell metabolism and transcriptional programs are hallmarks of cancer that sustain rapid proliferation and metastasis 1 . However, the mechanisms that control the interaction between metabolic reprogramming and transcriptional regulation remain unclear. Here we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) regulates transcriptional reprogramming by activating the oncogenic steroid receptor coactivator-3 (SRC-3). We used a kinome-wide RNA interference-based screening method to identify potential kinases that modulate the intrinsic SRC-3 transcriptional response. PFKFB4, a regulatory enzyme that synthesizes a potent stimulator of glycolysis 2 , is found to be a robust stimulator of SRC-3 that coregulates oestrogen receptor. PFKFB4 phosphorylates SRC-3 at serine 857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient Ser857Ala mutant SRC-3 abolishes the SRC-3-mediated transcriptional output. Functionally, PFKFB4-driven SRC-3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase. In addition, the two enzymes adenosine monophosphate deaminase-1 (AMPD1) and xanthine dehydrogenase (XDH), which are involved in purine metabolism, were identified as SRC-3 targets that may or may not be directly involved in purine synthesis. Mechanistically, phosphorylation of SRC-3 at Ser857 increases its interaction with the transcription factor ATF4 by stabilizing the recruitment of SRC-3 and ATF4 to target gene promoters. Ablation of SRC-3 or PFKFB4 suppresses breast tumour growth in mice and prevents metastasis to the lung from an orthotopic setting, as does Ser857Ala-mutant SRC-3. PFKFB4 and phosphorylated SRC-3 levels are increased and correlate in oestrogen receptor-positive tumours, whereas, in patients with the basal subtype, PFKFB4 and SRC-3 drive a common protein signature that correlates with the poor survival of patients with breast cancer. These findings suggest that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC-3 to promote aggressive metastatic tumours."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.org/dc/terms/identifier"doi:10.1038/s41586-018-0018-1"xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Choi J.M."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Zhang X.H."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Zhu B."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Jung S.Y."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Yi P."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Coarfa C."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"O'Malley B.W."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Dasgupta S."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Putluri N."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Tsai S.Y."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Tsai M.J."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Westbrook T.F."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Foulds C.E."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Nikolai B.C."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/author"Rajapakshe K."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/date"2018"xsd:gYear
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/name"Nature"xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/pages"249-254"xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/title"Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer."xsd:string
http://purl.uniprot.org/citations/29615789http://purl.uniprot.org/core/volume"556"xsd:string
http://purl.uniprot.org/citations/29615789http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/29615789
http://purl.uniprot.org/citations/29615789http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/29615789
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