当前位置: X-MOL 学术Nat. Genet. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.
Nature Genetics ( IF 31.7 ) Pub Date : 2018-Feb-01 , DOI: 10.1038/s41588-017-0026-3
Jingjing Chen 1, 2 , Ilaria Guccini 1 , Diletta Di Mitri 1 , Daniela Brina 1 , Ajinkya Revandkar 1, 2 , Manuela Sarti 1 , Emiliano Pasquini 1 , Abdullah Alajati 1 , Sandra Pinton 1 , Marco Losa 1 , Gianluca Civenni 1 , Carlo V Catapano 1 , Jacopo Sgrignani 3 , Andrea Cavalli 3 , Rocco D'Antuono 4 , John M Asara 5 , Andrea Morandi 6 , Paola Chiarugi 6 , Sara Crotti 7 , Marco Agostini 7, 8 , Monica Montopoli 9 , Ionica Masgras 10 , Andrea Rasola 10 , Ramon Garcia-Escudero 11, 12, 13 , Nicolas Delaleu 14 , Andrea Rinaldi 1 , Francesco Bertoni 1 , Johann de Bono 15 , Arkaitz Carracedo 13, 16, 17, 18 , Andrea Alimonti 1, 2, 19
Affiliation  

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.

中文翻译:

丙酮酸脱氢酶复合物的分隔活性维持前列腺癌中的脂肪生成。

线粒体代谢支持癌症合成代谢的机制仍不清楚。在这里,我们发现丙酮酸脱氢酶 A1 (PDHA1)(丙酮酸脱氢酶复合物 (PDC) 的一个亚基)的遗传和药理学失活通过影响脂质生物合成来抑制小鼠和人类异种移植肿瘤模型中前列腺癌的发展。从机制上讲,我们表明在前列腺癌中,PDC 定位于线粒体和细胞核中。核 PDC 通过介导组蛋白乙酰化来控制甾醇调节元件结合转录因子 (SREBF) 靶基因的表达,而线粒体 PDC 以协调的方式为脂质合成提供胞质柠檬酸盐,从而维持合成代谢。此外,我们发现 PDHA1 和 PDC 激活剂丙酮酸脱氢酶磷酸酶 1 (PDP1) 在前列腺肿瘤的基因和蛋白质水平上经常被扩增和过表达。总之,这些发现表明线粒体和核 PDC 都通过控制脂质生物合成来维持前列腺肿瘤的发生,因此表明这种复合物是癌症治疗的潜在靶点。
更新日期:2018-01-15
down
wechat
bug