Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
Cancer Biol Med. 2020 May 15;17(2):357-370. doi: 10.20892/j.issn.2095-3941.2019.0107.
The E3 ligase, CRL4, plays diverse roles in different cellular processes, such as DNA damage, transcriptional regulation, cell cycle progression, and cell apoptosis. Our previous study showed that CUL4A and CUL4B had a strong association with tobacco smoking risk in lung squamous cell carcinoma (SCC) and small cell lung carcinoma (SCLC). This study aimed to define the potential mechanism underlying the roles of CUL4A and CUL4B in the development of SCC and SCLC. We determined the role of CUL4A and CUL4B in the cell cycle and apoptosis of SCC and SCLC, and identified the key apoptosis-related gene involved in the oncogenic activity of CUL4B by Western blot, immunohistochemical staining, flow cytometry, and enzyme inhibition experiments. We found that depletion of CUL4A and CUL4B reduced the proliferation of SCC and SCLC cells. CUL4A but not CUL4B arrested cells in G1 phase while upregulating P21 and CUL4B promoted cell apoptosis through upregulation of FOXO3A. Accordingly, CUL4B decreased FOXO3A expression by activating the ERK signaling pathway and mediating FOXO3A degradation the ubiquitin-proteasome pathway. These results identified the function of E3 ligase CRL4 in regulating SCC and SCLC cell proliferation, which provides a potential strategy for cancer therapy by targeting FOXO3A and the E3 ligase, CRL4.
E3 连接酶 CRL4 在多种细胞过程中发挥着多样化的作用，如 DNA 损伤、转录调控、细胞周期进程和细胞凋亡。我们之前的研究表明，CUL4A 和 CUL4B 与肺鳞癌 (SCC) 和小细胞肺癌 (SCLC) 的吸烟风险有很强的关联。本研究旨在确定 CUL4A 和 CUL4B 在 SCC 和 SCLC 发展中的潜在作用机制。我们确定了 CUL4A 和 CUL4B 在 SCC 和 SCLC 细胞周期和凋亡中的作用，并通过 Western blot、免疫组织化学染色、流式细胞术和酶抑制实验鉴定了涉及 CUL4B 致癌活性的关键凋亡相关基因。我们发现，CUL4A 和 CUL4B 的耗竭降低了 SCC 和 SCLC 细胞的增殖。CUL4A 使细胞停滞在 G1 期，而 CUL4B 则通过上调 FOXO3A 促进细胞凋亡。因此，CUL4B 通过激活 ERK 信号通路并介导 FOXO3A 降解来减少 FOXO3A 的表达，该通路是泛素-蛋白酶体途径。这些结果确定了 E3 连接酶 CRL4 在调节 SCC 和 SCLC 细胞增殖中的作用，为通过靶向 FOXO3A 和 E3 连接酶 CRL4 进行癌症治疗提供了一种潜在策略。
