Titre
Molecular and Metabolic Characterization of Mitochondria Mediated Tumourigenesis in Prostate Cancer
Type
thèse de doctorat
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Auteur(s)
Chen, Jingjing
Auteure/Auteur
Directrices/directeurs
Alimonti, Andrea
Directeur⸱rice
Liens vers les personnes
Liens vers les unités
Faculté
Université de Lausanne, Faculté de biologie et médecine
Statut éditorial
Accepté
Date de publication
2018-03-07
Nombre de pages
98
Langue
anglais
Résumé
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.
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.
PID Serval
serval:BIB_E5396394C884
Date de création
2018-03-15T15:16:00.387Z
Date de création dans IRIS
2025-05-21T07:13:48Z
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Nom
Thesis-OK.pdf
Version du manuscrit
imprimatur
Taille
17.06 MB
Format
Adobe PDF
PID Serval
serval:BIB_E5396394C884.P002
URN
urn:nbn:ch:serval-BIB_E5396394C8843
Somme de contrôle
(MD5):f8347a0f8811b160a84daee2606ce0bb