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

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Serval ID
serval:BIB_93ADEEADA5CC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.
Journal
Nature genetics
Author(s)
Chen J., Guccini I., Di Mitri D., Brina D., Revandkar A., Sarti M., Pasquini E., Alajati A., Pinton S., Losa M., Civenni G., Catapano C.V., Sgrignani J., Cavalli A., D'Antuono R., Asara J.M., Morandi A., Chiarugi P., Crotti S., Agostini M., Montopoli M., Masgras I., Rasola A., Garcia-Escudero R., Delaleu N., Rinaldi A., Bertoni F., Bono J., Carracedo A., Alimonti A.
ISSN
1546-1718 (Electronic)
ISSN-L
1061-4036
Publication state
Published
Issued date
02/2018
Peer-reviewed
Oui
Volume
50
Number
2
Pages
219-228
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Animals, Cell Compartmentation/physiology, Cell Line, Tumor, Cell Nucleus/genetics, Cell Nucleus/metabolism, Cell Nucleus/pathology, Cells, Cultured, Cytoplasm/genetics, Cytoplasm/metabolism, Cytoplasm/pathology, Humans, Lipogenesis/genetics, Male, Mice, Mice, Knockout, Prostatic Neoplasms/genetics, Prostatic Neoplasms/metabolism, Prostatic Neoplasms/pathology, Protein Processing, Post-Translational/genetics, Pyruvate Dehydrogenase (Lipoamide)/genetics, Pyruvate Dehydrogenase (Lipoamide)/metabolism, Pyruvate Dehydrogenase Complex/metabolism, Pyruvate Dehydrogenase Complex/physiology
Pubmed
Web of science
Open Access
Yes
Create date
18/02/2018 23:04
Last modification date
21/05/2021 5:35
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