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Nat Genet. 2018 Feb;50(2):219-228. doi: 10.1038/s41588-017-0026-3. Epub 2018 Jan 15.

Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.

Author information

1
Institute of Oncology Research, Oncology Institute of Southern Switzerland, Università della Svizzera Italiana, Bellinzona, Switzerland.
2
Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
3
Computational Structural Biology, Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
4
Imaging Facility, Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
5
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
6
Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
7
Nano-inspired Biomedicine Lab, Institute of Paediatric Research-Città della Speranza, Padova, Italy.
8
Surgical Clinic, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.
9
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
10
CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Padova, Italy.
11
Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain.
12
Biomedical Research Institute I+12, University Hospital 12 de Octubre, Madrid, Spain.
13
Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
14
Roegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.
15
Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK.
16
CIC bioGUNE, Bizkaia Technology Park, Bizkaia, Spain.
17
Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
18
Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain.
19
Institute of Oncology Research, Oncology Institute of Southern Switzerland, Università della Svizzera Italiana, Bellinzona, Switzerland. andrea.alimonti@ior.iosi.ch.
20
Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. andrea.alimonti@ior.iosi.ch.
21
Department of Medicine, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy. andrea.alimonti@ior.iosi.ch.

Abstract

The mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus. Whereas nuclear PDC controls the expression of sterol regulatory element-binding transcription factor (SREBF)-target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated manner, thereby sustaining anabolism. Additionally, we found that PDHA1 and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1) are frequently amplified and overexpressed at both the gene and protein levels in prostate tumors. Together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy.

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