Department of Colorecal & Anal Surgery, The First Hospital of Jilin University, Changchun, P.R. China.
RNA Biol. 2021 Nov;18(11):1981-1995. doi: 10.1080/15476286.2021.1885232. Epub 2021 Feb 11.
NEDD4 is an E3 ubiquitin ligase that recognizes substrates through protein-protein interactions and is involved in cancer development. This study aimed to elucidate the function of NEDD4 in colon cancer (CC) progression and its mechanism of action. NEDD4 was abundantly expressed in CC tissues and cells, and the overexpression of NEDD4 promoted the growth and metastasis of xenograft tumours as well as the tumorigenesis rate of primary CC in mouse models. In experiments, the silencing (or upregulation) of NEDD4 inhibited (or increased) the viability, invasion, and epithelial-to-mesenchymal transition of CC cells. The binding relationships between NEDD4 and FOXA1, FOXA1 and microRNA (miRNA)-340-5p, and miR-340-5p and ATF1 were validated by Co-immunoprecipitation, chromatin immunoprecipitation and luciferase assays, and NEDD4 was demonstrated to trigger FOXA1 ubiquitination and degradation. FOXA1 transcriptionally activated miR-340-5p, which subsequently bound to ATF1 mRNA. The upregulation of FOXA1 or miR-340-5p or the downregulation of ATF1 blocked certain functions of NEDD4 in CC cells. Altogether, NEDD4 was demonstrated to trigger FOXA1 ubiquitination and promote CC progression under the involvement of microRNA-340-5p suppression and ATF1 upregulation.
NEDD4 是一种 E3 泛素连接酶，通过蛋白-蛋白相互作用识别底物，参与癌症的发生发展。本研究旨在阐明 NEDD4 在结肠癌（CC）进展中的作用及其作用机制。NEDD4 在 CC 组织和细胞中大量表达，过表达 NEDD4 促进异种移植瘤的生长和转移以及小鼠模型中原发性 CC 的肿瘤发生率。在实验中，沉默（或上调）NEDD4 抑制（或增加）CC 细胞的活力、侵袭和上皮-间充质转化。通过 Co-immunoprecipitation、chromatin immunoprecipitation 和 luciferase 测定验证了 NEDD4 与 FOXA1、FOXA1 与 microRNA（miRNA）-340-5p 以及 miR-340-5p 与 ATF1 之间的结合关系，并证实 NEDD4 触发 FOXA1 泛素化和降解。FOXA1 转录激活 miR-340-5p，随后与 ATF1 mRNA 结合。FOXA1 或 miR-340-5p 的上调或 ATF1 的下调阻断了 NEDD4 在 CC 细胞中的某些功能。总之，NEDD4 被证明在 microRNA-340-5p 抑制和 ATF1 上调的参与下触发 FOXA1 泛素化并促进 CC 进展。
