A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis.
A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis.
复制标题
DOI：
10.1126/science.1212728
复制
发表时间：
2012-01-20
期刊：
影响因子：
--
通讯作者：
Westbrook TF
中科院分区：
文献类型：
--
作者：
Kessler JD;Kahle KT;Sun T;Meerbrey KL;Schlabach MR;Schmitt EM;Skinner SO;Xu Q;Li MZ;Hartman ZC;Rao M;Yu P;Dominguez-Vidana R;Liang AC;Solimini NL;Bernardi RJ;Yu B;Hsu T;Golding I;Luo J;Osborne CK;Creighton CJ;Hilsenbeck SG;Schiff R;Shaw CA;Elledge SJ;Westbrook TF
Myc是一种致癌转录因子，在人类癌症中经常失调。为了确定支持Myc致癌程序的途径，我们采用了全基因组RNAi筛选Myc合成致死基因，并发现了SUMO激活酶（SAE 1/2）的作用。SAE 1/2酶活性的丧失驱动Myc的合成致死性。SAE 2的失活导致有丝分裂灾难和Myc超活化后选择性的细胞死亡。机械地，SAE 2抑制将Myc的转录子程序从激活切换到抑制。这些SUMO化依赖性Myc开关（SMS基因）的子集是有丝分裂纺锤体功能和支持Myc致癌程序所必需的。SAE 2是Myc依赖性肿瘤生长所必需的，患者生存期与Myc高肿瘤中的SAE 1/SAE 2水平显著相关。这些研究揭示了Myc驱动的癌症的有丝分裂脆弱性，证明抑制SUMO化损害Myc依赖性肿瘤发生，并表明抑制SUMO化可能对Myc驱动的癌症患者具有治疗益处。
Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we employed a genome-wide RNAi screen for Myc-synthetic-lethal genes and uncovered a role for the SUMO-activating-enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death selectively upon Myc hyper-activation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent-Myc-switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for Myc-dependent tumor growth, and patient survival significantly correlates with SAE1/SAE2 levels in Myc-high tumors. These studies reveal a mitotic vulnerability of Myc-driven cancers, demonstrate that inhibiting sumoylation impairs Myc-dependent tumorigenesis, and suggest inhibiting SUMOylation may have therapeutic benefits for patients with Myc-driven cancer.
登录
查看更多内容
影响因子：
11.2
作者：
Schmidt, Marcus;Boehm, Daniel;Gehrmann, Mathias
通讯作者：
Gehrmann, Mathias
影响因子：
64.8
作者：
Lowe, SW;Cepero, E;Evan, G
通讯作者：
Evan, G
影响因子：
64.5
作者：
Joukov, Vladimir;Groen, Aaron C.;Livingston, David M.
通讯作者：
Livingston, David M.
影响因子：
8.8
作者：
Deming SL;Nass SJ;Dickson RB;Trock BJ
通讯作者：
Trock BJ
影响因子：
56.9
作者：
HERMEKING, H;EICK, D
通讯作者：
EICK, D