Ki-67蛋白可准确反映肿瘤细胞的增殖活性，国内外尚未充分开展Ki-67蛋白代谢调控的相关研究。我们曾报道USP7去泛素化稳定Ki-67促进肺腺癌细胞增殖，目前仍不清楚Ki-67被泛素化的分子机制。近期我们发现细胞周期中Ki-67蛋白水平与APC/C-CDH1泛素连接酶复合物活性改变呈相反趋势；Ki-67氨基酸序列中有三个CDH1识别的KEN-box结构域；肺腺癌中Ki-67和CDH1蛋白表达负相关，USP4和CDH1蛋白表达正相关；肺腺癌细胞中过表达USP4时减弱CDH1蛋白泛素修饰，却增强Ki-67蛋白泛素修饰。由此提出假说：USP4通过稳定CDH1介导Ki-67泛素蛋白酶体降解抑制肺腺癌。拟研究Ki-67是APC/C-CDH1的靶蛋白；USP4稳定CDH1蛋白；USP4影响USP7对Ki-67去泛素化。这些研究有望为通过干预USP4与USP7加速Ki-67蛋白降解抑制肺腺癌提供线索。

Ki-67 protein can accurately reflect the proliferative activity of tumor cells. But related studies on the regulation of Ki-67 protein metabolism have not been fully carried out at home and abroad. We have reported that USP7 deubiquitination stabilizes Ki-67 to promote lung adenocarcinoma proliferation, but the molecular mechanism of Ki-67 ubiquitination is unclear. Recently, we found that Ki-67 protein levels and APC/C-CDH1 ubiquitin ligase complex activity show opposite trends during cell cycle progression. And there are three CDH1 recognized KEN-box domains in Ki-67 amino acid sequence. In the lung adenocarcinoma, the expression level of CDH1 protein was negatively correlated, and the expression level of USP4 and CDH1 protein was positively correlated. When USP4 was overexpressed in lung adenocarcinoma cells, the ubiquitin modification of CDH1 protein was attenuated, but the Ki-67 protein was enhanced. Based on this we propose a hypothesis: USP4 inhibits lung adenocarcinoma proliferation by stabilizing CDH-mediated Ki-67 ubiquitin proteasome degradation. Studies to be carried out: Ki-67 is a target protein of APC / C-CDH1; USP4 stabilizes CDH1 protein; USP4 affects Ki-67 deubiquitination of USP7. These studies are expected to provide clues for inhibiting lung adenocarcinoma proliferation by interfering with USP4 and USP7 to accelerate Ki-67 protein degradation.