Molecular and Metabolic Characterization of Mitochondria Mediated Tumourigenesis in Prostate Cancer

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Version: After imprimatur
Serval ID
serval:BIB_E5396394C884
Type
PhD thesis: a PhD thesis.
Collection
Publications
Institution
Title
Molecular and Metabolic Characterization of Mitochondria Mediated Tumourigenesis in Prostate Cancer
Author(s)
Chen Jingjing
Director(s)
Alimonti Andrea
Institution details
Université de Lausanne, Faculté de biologie et médecine
Address
Department of Biochemistry (DB)
Quartier UNIL-Epalinges
Ch. Des Boveresses 155
CP 51
CH-1066 Epalinges
Telephone: 021 692 57 00
Fax: 021 692 57 05
Publication state
Accepted
Issued date
07/03/2018
Language
english
Number of pages
98
Abstract
The mechanisms by which mitochondrial metabolism supports cancer anabolism are still
unclear. Here, we unexpectedly find that genetic and pharmacological inactivation of
Pyruvate Dehydrogenase A1 (PDHA1), a subunit of pyruvate dehydrogenase complex
(PDC) inhibits prostate cancer development in different mouse and human xenograft
tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate
cancer, PDC localizes in both mitochondria and nucleus. While 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 effort to sustain anabolism. In line with this evidence, we find
that PDHA1 and the PDC activator, Pyruvate dehydrogenase phosphatase 1 (PDP1), are
frequently amplified and overexpressed at both gene and protein level in prostate tumors.
Taken together, these findings demonstrate that both mitochondrial and nuclear PDC
sustain prostate tumorigenesis by controlling lipid biosynthesis thereby pointing at this
complex as a novel target for cancer therapy.
Create date
15/03/2018 16:16
Last modification date
20/08/2019 16:08
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