生物
丙酮酸脱氢酶复合物
丙酮酸脱氢酶激酶
脂肪生成
丙酮酸脱氢酶磷酸酶
前列腺癌
线粒体
脂质代谢
生物化学
细胞生物学
癌症
遗传学
酶
作者
Jingjing Chen,Ilaria Guccini,Diletta Di Mitri,Daniela Brina,Ajinkya Revandkar,Manuela Sarti,Emiliano Pasquini,Abdullah Alajati,Sandra Pinton,Marco Losa,Gianluca Civenni,Carlo V. Catapano,Jacopo Sgrignani,Andrea Cavalli,Rocco D’Antuono,John M. Asara,Andrea Morandi,Paola Chiarugi,Sara Crotti,Marco Agostini
出处
期刊:Nature Genetics
[Nature Portfolio]
日期:2018-01-05
卷期号:50 (2): 219-228
被引量:164
标识
DOI:10.1038/s41588-017-0026-3
摘要
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.
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