ZCCHC10 suppresses lung cancer progression and cisplatin resistance by attenuating MDM2-mediated p53 ubiquitination and degradation
ZCCHC10 suppresses lung cancer progression and cisplatin resistance by attenuating MDM2-mediated p53 ubiquitination and degradation
复制标题
DOI：
10.1038/s41419-019-1635-9
复制
发表时间：
2019-05-28
影响因子：
9
通讯作者：
Zhou, Jianlin
中科院分区：
文献类型：
--
作者：
Ning, Yichong;Hui, Na;Zhou, Jianlin
p53抑癌基因的激活对于防止细胞异常增殖和癌变是必不可少的。ZCCHC 10先前在酵母双杂交筛选中被鉴定为潜在的p53相互作用伴侣，但尚未研究细胞中的相互作用及其对p53活性和癌症发展的后续影响。在本文中，我们证明，ZCCHC 10的表达水平在肺腺癌组织中的统计学上低于相应的癌旁组织，ZCCHC 10 mRNA的表达降低预示着患者的生存较差。ZCCHC 10在携带野生型p53的肺癌细胞中的异位表达在体外显著抑制细胞增殖、集落形成、迁移、侵袭和顺铂抗性，以及在体内抑制肿瘤生长和转移。相反，ZCCHC 10的敲低在正常肺细胞Beas-2b中发挥相反的作用。ZCCHC 10对p53缺失型（H358）和p53突变型（H1437）肺癌细胞的生物学行为无影响。在机制上，ZCCHC 10通过破坏p53和MDM 2之间的相互作用来结合并稳定p53。p53抑制剂pifithrin-alpha减弱了ZCCHC 10过表达对p53通路、细胞周期、凋亡和上皮-间质转化的影响，而p53激活剂Nutlin 3可以逆转ZCCHC 10敲低的影响。总的来说，我们的研究结果表明，ZCCHC 10通过稳定p53蛋白发挥其肿瘤抑制作用，可用于肺腺癌的潜在预后标志物和治疗靶点。
The activation of p53 tumor suppressor is essential for preventing abnormal cell proliferation and carcinogenesis. ZCCHC10 was previously identified as a potential p53-interacting partner in a yeast two-hybrid screen, but the interaction in cells and its subsequent influence on p53 activity and cancer development have not been investigated. In this paper, we demonstrate that ZCCHC10 expression levels are statistically lower in lung adenocarcinoma tissues than the corresponding adjacent noncancerous tissues, and decreased expression of ZCCHC10 mRNA predicts poorer survival of the patients. Ectopic expression of ZCCHC10 in lung cancer cells harboring wild-type p53 dramatically suppresses cell proliferation, colony formation, migration, invasion and cisplatin resistance in vitro, as well as tumor growth and metastasis in vivo. Conversely, knockdown of ZCCHC10 exerts opposite effects in the normal lung cell Beas-2b. However, ZCCHC10 has no influence on the biological behaviors of p53-null (H358) or p53-mutant (H1437) lung cancer cells. Mechanistically, ZCCHC10 binds and stabilizes p53 by disrupting the interaction between p53 and MDM2. The p53 inhibitor pifithrin-alpha attenuated the influences of ZCCHC10 overexpression on p53 pathway, cell cycle, apoptosis, and epithelial-mesenchymal transition, whereas the p53 activator Nutlin3 could reverse the effects of ZCCHC10 knockdown. Collectively, our results indicate that ZCCHC10 exerts its tumor-suppressive effects by stabilizing the p53 protein and can be used a potential prognostic marker and therapeutic target in lung adenocarcinoma.