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

Subhamoy Dasgupta (), Kimal Rajapakshe, Bokai Zhu, Bryan C. Nikolai, Ping Yi, Nagireddy Putluri, Jong Min Choi, Sung Y. Jung, Cristian Coarfa, Thomas F. Westbrook, Xiang H.-F. Zhang, Charles E. Foulds, Sophia Y. Tsai, Ming-Jer Tsai and Bert W. O’Malley ()
Additional contact information
Subhamoy Dasgupta: Baylor College of Medicine
Kimal Rajapakshe: Baylor College of Medicine
Bokai Zhu: Baylor College of Medicine
Bryan C. Nikolai: Baylor College of Medicine
Ping Yi: Baylor College of Medicine
Nagireddy Putluri: Baylor College of Medicine
Jong Min Choi: Baylor College of Medicine
Sung Y. Jung: Baylor College of Medicine
Cristian Coarfa: Baylor College of Medicine
Thomas F. Westbrook: Baylor College of Medicine
Xiang H.-F. Zhang: Baylor College of Medicine
Charles E. Foulds: Baylor College of Medicine
Sophia Y. Tsai: Baylor College of Medicine
Ming-Jer Tsai: Baylor College of Medicine
Bert W. O’Malley: Baylor College of Medicine

Nature, 2018, vol. 556, issue 7700, 249-254

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0018-1

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