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

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Date
2018-02
ICR Author
De Bono, Johann
Author
Chen, J
Guccini, I
Di Mitri, D
Brina, D
Revandkar, A
Sarti, M
Pasquini, E
Alajati, A
Pinton, S
Losa, M
Civenni, G
Catapano, CV
Sgrignani, J
Cavalli, A
D'Antuono, R
Asara, JM
Morandi, A
Chiarugi, P
Crotti, S
Agostini, M
Montopoli, M
Masgras, I
Rasola, A
Garcia-Escudero, R
Delaleu, N
Rinaldi, A
Bertoni, F
Bono, JD
Carracedo, A
Alimonti, A
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/4223
DOI
https://doi.org/10.1038/s41588-017-0026-3
Collections
  • Clinical Studies
Subject
Cells, Cultured
Cell Line, Tumor
Cell Nucleus
Cytoplasm
Animals
Mice, Knockout
Humans
Mice
Prostatic Neoplasms
Pyruvate Dehydrogenase Complex
Pyruvate Dehydrogenase (Lipoamide)
Cell Compartmentation
Protein Processing, Post-Translational
Male
Lipogenesis
Research team
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2017-12-01
License start date
2018-02
Citation
Nature genetics, 2018, 50 (2), pp. 219 - 228

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