Ubiquitin specific peptidase 49 inhibits non-small cell lung cancer cell growth by suppressing PI3K/AKT signaling
Ubiquitin specific peptidase 49 inhibits non-small cell lung cancer cell growth by suppressing PI3K/AKT signaling
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DOI：
10.1002/kjm2.12073
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发表时间：
2019-07-01
影响因子：
3.3
通讯作者：
Zheng, Shi-Ying
中科院分区：
文献类型：
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作者：
Shen, Wen-Ming;Yin, Jin-Nan;Zheng, Shi-Ying
泛素特异性多肽酶49(USP49)在多种肿瘤中具有抑癌作用，但其在非小细胞肺癌(NSCLC)中的作用及其分子机制尚不清楚。在这项研究中，USP49在NSCLC原发组织和细胞系中表达下调，USP49的高表达预示着NSCLC患者的总体生存指数呈阳性。USP49过表达下调Cyclin D1的表达水平，上调P53的表达。进一步的流式细胞仪分析显示，过表达USP49可诱导细胞周期停滞于G0/G1期。结果表明，USP49过表达显著抑制了NSCLC细胞的生长。在机制上，USP49的过表达抑制了PI3K/AKT信号转导，而USP49的敲除则增强了这一信号转导。进一步研究表明，USP49去泛素化PTEN并稳定PTEN蛋白，提示USP49通过稳定PTEN而抑制PI3K/AKT信号转导。综上所述，我们证实了USP49在NSCLC细胞中的功能，并通过抑制PI3K/AKT信号通路抑制NSCLC细胞的生长，提示USP49可能成为治疗NSCLC的新靶点。
Ubiquitin specific peptidase 49 (USP49) has been reported as a tumor suppressor in several tumors, but its function and molecular mechanism in non-small cell lung cancer (NSCLC) are still unknown. In this study, USP49 was found downregulated in NSCLC primary tissues and cell lines, and high USP49 predicted a positive index for the overall survival of NSCLC patients. Overexpression of USP49 downregulated the expression levels of Cyclin D1, and upregulated p53 expression. Further flow cytometry analysis showed that overexpressed USP49 induced cell cycle arrest at G0/G1 phase. As a result, overexpression of USP49 significantly inhibited cell growth of NSCLC cells. In mechanism, overexpression of USP49 inhibited PI3K/AKT signaling, but knockdown of USP49 enhanced this signaling. Further studies indicated that USP49 deubiquitinated PTEN and stabilized PTEN protein, which suggested that USP49 inhibited PI3K/AKT signaling by stabilizing PTEN in NSCLC cells. In conclusion, we demonstrated that USP49 was functional in NSCLC cells, and inhibited NSCLC cell growth by suppressing PI3K/AKT signaling, suggesting that USP49 could be as a novel target for NSCLC therapy.