Authors' Affiliations: Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education; Department of Biochemistry and Molecular Biology, Shandong University School of Medicine; Department of Respiratory Medicine, Qilu Hospital, Shandong University, Jinan; International Biotechnology R&D Center, Shandong University School of Ocean, Weihai, Shandong, China; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley; Department of Pathology; Thoracic Oncology Laboratory, Department of Surgery; Helen Diller Family Comprehensive Cancer Center and Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California; and Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon.
Cancer Res. 2014 Jan 15;74(2):520-31. doi: 10.1158/0008-5472.CAN-13-2182. Epub 2013 Dec 4.
The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.
泛素连接酶 CUL4A 被认为与肿瘤发生有关，但它对肿瘤进展和转移的贡献尚未得到评估。在这里，我们表明 CUL4A 在乳腺癌以及卵巢癌、胃癌和结直肠癌中升高，其表达水平与远处转移呈正相关。在正常或恶性人乳腺上皮细胞中过表达 CUL4A 会增加其体外和体内的肿瘤特性，显著增加上皮-间充质转化 (EMT) 和恶性细胞的转移能力。相比之下，沉默侵袭性乳腺癌细胞中的 CUL4A 会抑制这些过程。从机制上讲，我们发现 CUL4A 以与其转录相关的方式调节 EMT 调节基因 ZEB1 启动子处的组蛋白 H3K4me3。沉默 ZEB1 会阻断 CUL4A 驱动的增殖、EMT、肿瘤发生和转移。此外，在人类乳腺癌中，ZEB1 的表达与 CUL4A 的表达和远处转移呈正相关。总之，我们的研究结果揭示了 CUL4A 在调节乳腺癌细胞转移行为中的关键作用。
