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

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 tumour 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 these 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 tumours. Taken together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumourigenesis by controlling lipid biosynthesis thereby pointing at this complex as a novel target for cancer therapy.

STAT3‐dependent analysis revealsPDK4as independent predictor of recurrence in prostate cancer

“…Yang et al show that down‐regulation of PDK4 is associated with earlier recurrence and lower survival time in hepatocellular carcinoma (Yang et al , ). In concurrence with our data, Chen et al () show that prostate tumors exhibit higher gene expression and higher protein levels of both PDC subunit pyruvate dehydrogenase A1 (PDHA1) and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1). Mengual et al find PDK4 to be significantly differentially expressed in both tumors and post‐prostatic massage urine samples from PCa patients compared to the respective control groups (Mengual et al , ).…”

STAT3-dependent systems-level analysis revealsPDK4as an independent predictor of biochemical recurrence in prostate cancer

“…Yang et al show that downregulation of PDK4 is associated with earlier recurrence and lower survival time in hepatocellular carcinoma (Yang et al, 2019). In concurrence with our data, Chen et al (Chen et al, 2018) show that prostate tumors exhibit higher gene expression and higher protein levels of both PDC subunit pyruvate dehydrogenase A1 (PDHA1) and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1). Mengual et al find PDK4 to be significantly higher expressed in both tumors and post-prostatic massage urine samples from PCa patients compared to the respective control groups (Mengual et al, 2014).…”

PYCR1-dependent proline synthesis in cancer-associated fibroblasts is required for the deposition of pro-tumorigenic extracellular matrix

“…MS tracing experiments using uniformly 13 Clabelled glucose, glutamine, palmitate or pyruvate showed that over 70% of acetyl-CoA was derived from glucose or pyruvate, both of which are converted to acetyl-CoA via PDC (Figure 2a and Extended Data Figure Sa). There is evidence that PDC can translocate into the nucleus to synthesise acetyl-CoA in loco 41,42 , but we excluded this mechanism in CAFs because we detected the majority of PDHA1 in the mitochondria, by immunofluorescence staining of fixed cells and western blot analysis of mitochondria (Extended Data Figure 2b,c). Tracing experiments with 13 C 6 -glucose additionally indicated that PDC-derived acetyl-CoA was likely to be transported into the cytosol, because only a minimal portion of 13 C-labelled citrate was funnelled into the TCA cycle (Extended Data Figure 2d,e).…”