Functional genomics reveal that the serine synthesis pathway is essential in breast cancer.
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer.
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DOI：
10.1038/nature10350
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发表时间：
2011-08-18
期刊：
影响因子：
64.8
通讯作者：
Sabatini, David M.
中科院分区：
文献类型：
--
作者：
Possemato, Richard;Marks, Kevin M.;Shaul, Yoav D.;Pacold, Michael E.;Kim, Dohoon;Birsoy, Kivanc;Sethumadhavan, Shalini;Woo, Hin-Koon;Jang, Hyun G.;Jha, Abhishek K.;Chen, Walter W.;Barrett, Francesca G.;Stransky, Nicolas;Tsun, Zhi-Yang;Cowley, Glenn S.;Barretina, Jordi;Kalaany, Nada Y.;Hsu, Peggy P.;Ottina, Kathleen;Chan, Albert M.;Yuan, Bingbing;Garraway, Levi A.;Root, David E.;Mino-Kenudson, Mari;Brachtel, Elena F.;Driggers, Edward M.;Sabatini, David M.
癌细胞调整其代谢过程，以驱动大分子生物合成，以实现细胞的快速生长和增殖。基于RNAi的功能缺失筛查已被证明是识别新的和有趣的癌症靶点的有效方法，最近的研究利用这一技术在体内识别新的肿瘤抑制基因。在这里，我们开发了一种方法，通过在实体瘤中进行负选择RNAi筛查来识别新的癌症靶点。使用这种方法，我们筛选了一组与侵袭性乳腺癌和干性相关的代谢基因，以确定体内肿瘤发生所需的基因。在已鉴定的基因中，磷酸甘油脱氢酶(PHGDH)位于乳腺癌基因组中经常性拷贝数增加的区域，在70%的ER阴性乳腺癌中，PHGDH蛋白水平升高。PHGDH催化丝氨酸生物合成途径的第一步，高表达PHGDH的乳腺癌细胞丝氨酸合成通量增加。在PHGDH表达升高的细胞系中抑制PHGDH，但不是那些没有表达的细胞系，会导致细胞增殖和丝氨酸合成的强烈下降。我们发现，PHGDH抑制不影响细胞内丝氨酸水平，但导致α-酮戊二酸水平下降，α-酮戊二酸是该途径的另一种产物，也是TCA循环的中间产物。在PHGDH高表达的细胞中，丝氨酸合成途径为TCA循环贡献了大约50%的谷氨酰胺逆行通量。这些结果揭示了某些乳腺癌依赖于PHGDH过表达引起的丝氨酸途径通量的增加，并证明了体内负选择RNAi筛选在寻找潜在的抗癌靶点方面的有效性。
Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNAi-based loss of function screening has proven powerful for the identification of novel and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumor suppressor genes. Here, we developed a method for identifying novel cancer targets via negative selection RNAi screening in solid tumours. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumourigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of ER-negative breast cancers. PHGDH catalyzes the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have elevations in serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of alpha-ketoglutarate, another output of the pathway and a TCA cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH over-expression and demonstrate the utility of in vivo negative selection RNAi screens for finding potential anticancer targets.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
影响因子：
64.5
作者：
Marson A;Levine SS;Cole MF;Frampton GM;Brambrink T;Johnstone S;Guenther MG;Johnston WK;Wernig M;Newman J;Calabrese JM;Dennis LM;Volkert TL;Gupta S;Love J;Hannett N;Sharp PA;Bartel DP;Jaenisch R;Young RA
通讯作者：
Young RA
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
158.5
作者：
van de Vijver, MJ;He, YD;Bernards, R
通讯作者：
Bernards, R