Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Department of Emergency Surgery, The Affiliated Wujin People's Hospital of Jiangsu University, Changzhou, Jiangsu, China.
Kaohsiung J Med Sci. 2019 Jul;35(7):401-407. doi: 10.1002/kjm2.12073. Epub 2019 Apr 18.
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.
泛素特异性肽酶 49（USP49）已在多种肿瘤中被报道为肿瘤抑制因子，但它在非小细胞肺癌（NSCLC）中的功能和分子机制尚不清楚。在本研究中，发现 USP49 在 NSCLC 原发组织和细胞系中下调，高 USP49 预测 NSCLC 患者总生存率呈阳性指数。USP49 的过表达下调了 Cyclin D1 的表达水平，并上调了 p53 的表达。进一步的流式细胞术分析表明，过表达 USP49 诱导细胞周期停滞在 G0/G1 期。结果，过表达 USP49 显著抑制 NSCLC 细胞的生长。在机制上，过表达 USP49 抑制了 PI3K/AKT 信号通路，但 USP49 的敲低增强了这种信号通路。进一步的研究表明，USP49 去泛素化了 PTEN 并稳定了 PTEN 蛋白，这表明 USP49 通过在 NSCLC 细胞中稳定 PTEN 来抑制 PI3K/AKT 信号通路。总之，我们证明了 USP49 在 NSCLC 细胞中具有功能，通过抑制 PI3K/AKT 信号通路抑制 NSCLC 细胞生长，提示 USP49 可能成为 NSCLC 治疗的新靶点。
