The deubiquitinase USP28 stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells.
The deubiquitinase USP28 stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells.
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DOI：
10.1016/j.celrep.2013.08.030
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发表时间：
2013-10-17
期刊：
影响因子：
8.8
通讯作者：
Zhou BP
中科院分区：
文献类型：
--
作者：
Wu Y;Wang Y;Yang XH;Kang T;Zhao Y;Wang C;Evers BM;Zhou BP
LSD1是一种重要的染色质调节剂，通过H3K4me1/2的去甲基化来控制细胞的多能性和分化。LSD1在许多类型的肿瘤中都有过表达，并与其在肿瘤发生中的致癌作用有关。然而，导致LSD1在肿瘤中上调的机制尚不清楚。使用针对所有人类去泛素酶的无偏向siRNA筛选，我们确定USP28是LSD1的一个真正的去泛素酶。USP28通过去泛素化与LSD1相互作用并稳定LSD1。USP28的过度表达与LSD1在多个癌细胞系和乳腺肿瘤样本中的上调相关。USP28的敲除导致LSD1失稳，导致体外抑制肿瘤干细胞(CSC)样特性和体内致瘤性，这可以通过异位表达LSD1来挽救。我们的研究揭示了USP28表观遗传调控的关键机制，并提供了一种新的乳腺癌治疗方法。
LSD1 is a critical chromatin modulator controlling cellular pluripotency and differentiation through the demethylation of H3K4me1/2. Overexpression of LSD1 has been observed in many types of tumors and is correlated with its oncogenic effects in tumorigenesis. However, the mechanism leading to LSD1 upregulation in tumors remains unclear. Using an unbiased siRNA screening against all the human deubiquitinases, we identified USP28 as a bona fide deubiquitinase of LSD1. USP28 interacted with and stabilized LSD1 via deubiquitination. USP28 overexpression correlated with LSD1 upregulation in multiple cancer cell lines and breast tumor samples. Knockdown of USP28 resulted in LSD1 destabilization, leading to the suppression of cancer stem cell (CSC)-like characteristics in vitro and inhibition of tumorigenicity in vivo, which can be rescued by ectopic LSD1 expression. Our study reveals a critical mechanism underlying the epigenetic regulation by USP28 and provides a new treatment approach against breast cancer.
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DOI：
10.1186/bcr1673
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Fillmore C;Kuperwasser C
通讯作者：
Kuperwasser C
影响因子：
16
作者：
Mulligan P;Yang F;Di Stefano L;Ji JY;Ouyang J;Nishikawa JL;Toiber D;Kulkarni M;Wang Q;Najafi-Shoushtari SH;Mostoslavsky R;Gygi SP;Gill G;Dyson NJ;Näär AM
通讯作者：
Näär AM
影响因子：
8.8
作者：
Plaks V;Brenot A;Lawson DA;Linnemann JR;Van Kappel EC;Wong KC;de Sauvage F;Klein OD;Werb Z
通讯作者：
Werb Z
影响因子：
64.8
作者：
Brummelkamp, TR;Nijman, SMB;Bernards, R
通讯作者：
Bernards, R
DOI：
10.1073/pnas.0400699101
发表时间：
2004-03-23
影响因子：
11.1
作者：
Liu, BY;McDermott, SP;Alexander, CM
通讯作者：
Alexander, CM