Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer

Nature. 2018 Apr;556(7700):249-254. doi: 10.1038/s41586-018-0018-1. Epub 2018 Apr 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Glucose / metabolism*
  • Glycolysis
  • Humans
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Mice
  • Neoplasm Metastasis
  • Nuclear Receptor Coactivator 3 / metabolism*
  • Pentose Phosphate Pathway
  • Phosphofructokinase-2 / metabolism*
  • Phosphorylation
  • Phosphoserine / metabolism
  • Prognosis
  • Purines / biosynthesis
  • Purines / metabolism
  • RNA Interference
  • Receptors, Estrogen / metabolism
  • Transcriptional Activation*
  • Transketolase / metabolism
  • Xenograft Model Antitumor Assays


  • ATF4 protein, human
  • PFKFB4 protein, human
  • Purines
  • Receptors, Estrogen
  • Activating Transcription Factor 4
  • Phosphoserine
  • Transketolase
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • Phosphofructokinase-2
  • Glucose
  • purine