Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China.
Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100730 Beijing, China.
Gene. 2020 Oct 20;758:144960. doi: 10.1016/j.gene.2020.144960. Epub 2020 Jul 17.
As a member of the ubiquitin-specific protease (USP) family, USP22 could remove ubiquitin moieties from its target proteins to control the function of the target proteins. Accumulating studies show that USP22 essentially participates in diverse types of cancer as an oncogene-like protein. However, the roles of USP22 in human pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanism are unknown. Here we report that USP22 promotes the growth of PDAC cells by promoting the expression of dual-specificity tyrosine regulated kinase 1A (DYRK1A). Our results showed that the expression levels of USP22 were up-regulated in human PDAC tissues and cell lines (BxPC-3, AsPC-1, MIA-PaCa-2, PANC-1, and CAPAN-1). Lentivirus-mediated knockdown of USP22 repressed the rate of proliferation and capacity of colony formation of BxPC3 and CAPAN1 cancer cells and USP22 overexpression promoted the proliferation and capacity of the colony formation of BxPC3 and CAPAN1 cancer cells. The further mechanism study showed that USP22 elevated the expression of the mRNA and protein levels of DYRK1A in PDAC cancer cells. Inhibition of DYRK1A with EHT-5732 or lentivirus-mediated knockdown of DYRK1A blocked the function of USP22 overexpression in the regulation of the proliferation and colony formation of PDAC cells. Taken together, our findings demonstrated that USP22 overexpression in PDAC promoted the growth of the cancer cells partially through upregulating the expression of DYRK1A.
作为泛素特异性蛋白酶 (USP) 家族的一员，USP22 可以从其靶蛋白上去除泛素部分，从而控制靶蛋白的功能。越来越多的研究表明，USP22 作为癌基因样蛋白，在多种类型的癌症中起着至关重要的作用。然而，USP22 在人胰腺导管腺癌 (PDAC) 中的作用及其潜在机制尚不清楚。在这里，我们报告 USP22 通过促进双特异性酪氨酸调节激酶 1A (DYRK1A) 的表达来促进 PDAC 细胞的生长。我们的结果表明，USP22 在人 PDAC 组织和细胞系（BxPC-3、AsPC-1、MIA-PaCa-2、PANC-1 和 CAPAN-1）中表达上调。慢病毒介导的 USP22 敲低抑制了 BxPC3 和 CAPAN1 癌细胞的增殖率和集落形成能力，而过表达 USP22 则促进了 BxPC3 和 CAPAN1 癌细胞的增殖和集落形成能力。进一步的机制研究表明，USP22 上调了 PDAC 癌细胞中 DYRK1A 的 mRNA 和蛋白水平表达。用 EHT-5732 抑制 DYRK1A 或用慢病毒介导的 DYRK1A 敲低阻断了 USP22 过表达在调节 PDAC 细胞增殖和集落形成中的作用。总之，我们的研究结果表明，PDAC 中 USP22 的过表达部分通过上调 DYRK1A 的表达促进了癌细胞的生长。
