Amplification of USP13 drives ovarian cancer metabolism.
Amplification of USP13 drives ovarian cancer metabolism.
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DOI：
10.1038/ncomms13525
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发表时间：
2016-11-28
影响因子：
16.6
通讯作者：
Lu, Xiongbin
中科院分区：
文献类型：
--
作者：
Han, Cecil;Yang, Lifeng;Choi, Hyun Ho;Baddour, Joelle;Achreja, Abhinav;Liu, Yunhua;Li, Yujing;Li, Jiada;Wan, Guohui;Huang, Cheng;Ji, Guang;Zhang, Xinna;Nagrath, Deepak;Lu, Xiongbin
最近，能量代谢失调被认为是癌症的一个标志。尽管代谢酶的突变将代谢与肿瘤发生联系起来，但它们在卵巢癌中相对罕见。更常见的是，癌症代谢是通过改变代谢酶的丰度和活性来重新设计的。在这里，我们确定泛素特异性肽酶 13 (USP13) 是驱动卵巢癌代谢的主要调节因子。 USP13 特异性地去泛素化，从而上调 ATP 柠檬酸裂解酶和氧化戊二酸脱氢酶，这两种酶决定线粒体呼吸、谷氨酰胺分解和脂肪酸合成。 USP13 基因在 29.3% 的高级别浆液性卵巢癌中与 PIK3CA 共同扩增，其过度表达与不良临床结果显着相关。抑制 USP13 可显着抑制卵巢肿瘤进展并使肿瘤细胞对 PI3K/AKT 抑制剂的治疗敏感。我们的结果揭示了 USP13 以代谢为中心的重要作用，这可能会导致针对卵巢癌的 USP13 的潜在治疗。 癌细胞需要重新编程其新陈代谢以允许细胞快速增殖。在这里，作者表明 USP13 在卵巢癌中被扩增，其蛋白质产物（一种去泛素酶）通过稳定两种关键的代谢酶来重新连接癌细胞的代谢，从而驱动肿瘤进展。
Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis. The USP13 gene is co-amplified with PIK3CA in 29.3% of high-grade serous ovarian cancers and its overexpression is significantly associated with poor clinical outcome. Inhibiting USP13 remarkably suppresses ovarian tumour progression and sensitizes tumour cells to the treatment of PI3K/AKT inhibitor. Our results reveal an important metabolism-centric role of USP13, which may lead to potential therapeutics targeting USP13 in ovarian cancers. Cancer cells need to reprogramme their metabolism to allow rapid cell proliferation. Here, the authors show that USP13 is amplified in ovarian cancer and its protein product, a deubiquitinase, drives tumour progression by rewiring the metabolism of cancer cells by stabilising two critical metabolic enzymes.
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影响因子：
30.8
作者：
Bard-Chapeau, Emilie A.;Nguyen, Anh-Tuan;Rust, Alistair G.;Sayadi, Ahmed;Lee, Philip;Chua, Belinda Q.;New, Lee-Sun;de Jong, Johann;Ward, Jerrold M.;Chin, Christopher K. Y.;Chew, Valerie;Han Chong Toh;Abastado, Jean-Pierre;Benoukraf, Touati;Soong, Richie;Bard, Frederic A.;Dupuy, Adam J.;Johnson, Randy L.;Radda, George K.;Chan, Eric Chun Yong;Wessels, Lodewyk F. A.;Adams, David J.;Jenkins, Nancy A.;Copeland, Neal G.
通讯作者：
Copeland, Neal G.
影响因子：
28.2
作者：
Hanrahan AJ;Schultz N;Westfal ML;Sakr RA;Giri DD;Scarperi S;Janakiraman M;Olvera N;Stevens EV;She QB;Aghajanian C;King TA;Stanchina Ed;Spriggs DR;Heguy A;Taylor BS;Sander C;Rosen N;Levine DA;Solit DB
通讯作者：
Solit DB
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
Beclin1 通过调节 USP10 和 USP13 的去泛素化活性来控制 p53 的水平。
影响因子：
64.5
作者：
Liu J;Xia H;Kim M;Xu L;Li Y;Zhang L;Cai Y;Norberg HV;Zhang T;Furuya T;Jin M;Zhu Z;Wang H;Yu J;Li Y;Hao Y;Choi A;Ke H;Ma D;Yuan J
通讯作者：
Yuan J
影响因子：
21.3
作者：
Boroughs LK;DeBerardinis RJ
通讯作者：
DeBerardinis RJ