Ubiquitin C-Terminal Hydrolase-L1 Potentiates Cancer Chemosensitivity by Stabilizing NOXA
Ubiquitin C-Terminal Hydrolase-L1 Potentiates Cancer Chemosensitivity by Stabilizing NOXA
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DOI：
10.1016/j.celrep.2013.02.014
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发表时间：
2013-03-01
期刊：
影响因子：
8.8
通讯作者：
Kashkar, Hamid
中科院分区：
文献类型：
--
作者：
Brinkmann, Kerstin;Zigrino, Paola;Kashkar, Hamid
仅BH 3蛋白NOXA代表DNA损伤诱导的细胞死亡的关键介质之一。特别是，它参与细胞对癌症化疗的反应越来越明显。在这里，我们确定了一种策略，癌细胞逃避遗传毒性化疗增加蛋白酶体降解NOXA。我们发现去泛素化酶UCH-L1是NOXA周转的关键调节因子，它通过去除赖氨酸（48）连接的多聚泛素链来保护NOXA免受蛋白酶体降解。在大多数患有高化疗耐药率的黑色素瘤或结直肠癌患者的肿瘤中，NOXA未能积累，因为UCH-L1表达在表观遗传学上被沉默。尽管UCH-L1/NOXA阳性肿瘤样本对遗传毒性化疗的敏感性增加，但下调UCH-L1或抑制其去泛素化酶活性导致NOXA稳定性降低，并对人类和C.线虫细胞我们的数据将UCH-L1/NOXA相互作用确定为克服癌症化疗耐药性的治疗靶点。
The BH3-only protein NOXA represents one of the critical mediators of DNA-damage-induced cell death. In particular, its involvement in cellular responses to cancer chemotherapy is increasingly evident. Here, we identify a strategy of cancer cells to escape genotoxic chemotherapy by increasing proteasomal degradation of NOXA. We show that the deubiquitylating enzyme UCH-L1 is a key regulator of NOXA turnover, which protects NOXA from proteasomal degradation by removing Lys(48)-linked polyubiquitin chains. In the majority of tumors from patients with melanoma or colorectal cancer suffering from high rates of chemoresistance, NOXA fails to accumulate because UCH-L1 expression is epigenetically silenced. Whereas UCH-L1/NOXA-positive tumor samples exhibit increased sensitivity to genotoxic chemotherapy, downregulation of UCH-L1 or inhibition of its deubiquitylase activity resulted in reduced NOXA stability and resistance to genotoxic chemotherapy in both human and C. elegans cells. Our data identify the UCH-L1/NOXA interaction as a therapeutic target for overcoming cancer chemoresistance.