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.