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

• Published in: Nature genetics Vol. 50; no. 2; pp. 219 - 228
• Main Authors: Chen, Jingjing, Guccini, Ilaria, Di Mitri, Diletta, Brina, Daniela, Revandkar, Ajinkya, Sarti, Manuela, Pasquini, Emiliano, Alajati, Abdullah, Pinton, Sandra, Losa, Marco, Civenni, Gianluca, Catapano, Carlo V., Sgrignani, Jacopo, Cavalli, Andrea, D’Antuono, Rocco, Asara, John M., Morandi, Andrea, Chiarugi, Paola, Crotti, Sara, Agostini, Marco, Montopoli, Monica, Masgras, Ionica, Rasola, Andrea, Garcia-Escudero, Ramon, Delaleu, Nicolas, Rinaldi, Andrea, Bertoni, Francesco, Bono, Johann de, Carracedo, Arkaitz, Alimonti, Andrea
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2018; Nature Publishing Group
• Subjects: 101/58; 13/1; 13/105; 13/109; 13/44; 13/51; 13/89; 14/19; 14/34; 14/63; 38/39; 45/15; 631/208/176; 631/45/320; 64/110; 64/60; 692/308/1426; 692/699/67/589/466; 96/2; Acetylation; Agriculture; Animal Genetics and Genomics; Animal models; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Cancer Research; Cell Compartmentation - physiology; Cell growth; Cell Line, Tumor; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cells, Cultured; Citric acid; Cytoplasm - genetics; Cytoplasm - metabolism; Cytoplasm - pathology; Datasets; Deactivation; Dehydrogenase; Dehydrogenases; Diagnosis; Gene expression; Gene Function; Genes; Genetic aspects; Human Genetics; Humans; Inactivation; Kinases; Lipids; Lipogenesis; Lipogenesis - genetics; Male; Metabolism; Mice; Mice, Knockout; Mitochondria; Pharmacology; Phosphatases; Phosphorylation; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Processing, Post-Translational - genetics; Proteins; Pyruvate dehydrogenase (lipoamide); Pyruvate Dehydrogenase (Lipoamide) - genetics; Pyruvate Dehydrogenase (Lipoamide) - metabolism; Pyruvate dehydrogenase complex; Pyruvate Dehydrogenase Complex - metabolism; Pyruvate Dehydrogenase Complex - physiology; Pyruvic acid; Regulatory sequences; Respiration; Steroids (Organic compounds); Transcription (Genetics); Tumorigenesis; Tumors; Xenografts; Xenotransplantation; Spain
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-017-0026-3

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. Inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC) regulating mitochondrial metabolism, inhibits lipid biosynthesis and prostate cancer development in mouse and human xenograft tumor models.