OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination.
OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination.
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DOI：
10.15252/emmm.201505972
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发表时间：
2016-03-01
影响因子：
11.1
通讯作者：
Sablina AA
中科院分区：
文献类型：
--
作者：
Baietti MF;Simicek M;Abbasi Asbagh L;Radaelli E;Lievens S;Crowther J;Steklov M;Aushev VN;Martínez García D;Tavernier J;Sablina AA
RAS致癌途径的激活通常由RAS基因突变引起，在人类癌症中是一种常见的事件。最近的报道表明，RAS GTP酶的可逆泛素化显著影响其活性，提示参与调节RAS泛素化的酶可能有助于恶性转化。在这里，我们确定去泛素酶OTUB1是RAS单泛素化和双泛素化的负调控因子。OTUB1独立于其催化活性抑制RAS泛素化，导致RAS滞留在质膜上。OTUB1促进野生型RAS细胞中RAS的激活和肿瘤的发生。在携带野生型KRAS的非小细胞肺癌中，通常可以观察到OTUB1表达的增加，并与ERK1/2磷酸化水平升高、Ki67评分高以及患者生存较差有关。我们的结果有力地表明，RAS泛素化的失调是肺癌发生过程中RAS激活的另一种机制。
Activation of the RAS oncogenic pathway, frequently ensuing from mutations in RAS genes, is a common event in human cancer. Recent reports demonstrate that reversible ubiquitination of RAS GTPases dramatically affects their activity, suggesting that enzymes involved in regulating RAS ubiquitination may contribute to malignant transformation. Here, we identified the de‐ubiquitinase OTUB1 as a negative regulator of RAS mono‐ and di‐ubiquitination. OTUB1 inhibits RAS ubiquitination independently of its catalytic activity resulting in sequestration of RAS on the plasma membrane. OTUB1 promotes RAS activation and tumorigenesis in wild‐type RAS cells. An increase of OTUB1 expression is commonly observed in non‐small‐cell lung carcinomas harboring wild‐type KRAS and is associated with increased levels of ERK1/2 phosphorylation, high Ki67 score, and poorer patient survival. Our results strongly indicate that dysregulation of RAS ubiquitination represents an alternative mechanism of RAS activation during lung cancer development.