Wang Xiujuan, Gong Yanbing, Jin Bo, Wu Chenglin, Yang Jianming, Wang Le, Zhang Zheng, Mao Zebin
Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, Beijing 100191, P.R. China.
Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China.
Oncol Rep. 2014 Sep;32(3):1281-90. doi: 10.3892/or.2014.3309. Epub 2014 Jul 3.
Long non-coding RNA urothelial carcinoma associated 1 (UCA1) was first identified in bladder cancer tissues. High expression of UCA1 in bladder cancer has suggested it may serve as a potential diagnostic molecular marker for bladder cancer. Subsequent research in bladder cancer cell lines showed that UCA1 can promote cell proliferation, but the underlying mechanism remains unknown. In the present study, we identified BRG1 as a UCA1 binding partner using an in vitro RNA pull-down assay, and RNA-binding protein immunoprecipitation assay confirmed UCA1-BRG binding in bladder cancer cells in vivo. BRG1 is a chromatin remodeling factor with reported tumor suppressor activities that directly upregulates levels of the p21 cell cycle inhibitor by binding sequences in the p21 promoter. Depletion of UCA1 by RNAi resulted in upregulated p21 levels and inhibition of cell replication, while overexpressed UCA1 reduced p21 protein and promoted cell growth. Notably, UCA1 downregulation of p21 and induction of cell proliferation antagonized the function of BRG1. UCA1 highly expressed tissue samples are often with BRG1 high expression. Furthermore, we found that UCA1 impairs both binding of BRG1 to the p21 promoter and chromatin remodeling activity of BRG1. Collectively, these results demonstrate that UCA1 promotes bladder cancer cell proliferation by inhibiting BRG1.
长链非编码RNA尿路上皮癌相关1（UCA1）最初是在膀胱癌组织中被鉴定出来的。UCA1在膀胱癌中的高表达表明它可能作为膀胱癌潜在的诊断分子标志物。随后在膀胱癌细胞系中的研究表明，UCA1可以促进细胞增殖，但其潜在机制仍不清楚。在本研究中，我们通过体外RNA下拉试验鉴定出BRG1是UCA1的结合伙伴，并且RNA结合蛋白免疫沉淀试验证实了UCA1与BRG在体内膀胱癌细胞中的结合。BRG1是一种染色质重塑因子，据报道具有肿瘤抑制活性，它通过结合p21启动子中的序列直接上调p21细胞周期抑制剂的水平。通过RNA干扰使UCA1缺失导致p21水平上调并抑制细胞复制，而过度表达UCA1则降低p21蛋白水平并促进细胞生长。值得注意的是，UCA1对p21的下调和对细胞增殖的诱导拮抗了BRG1的功能。UCA1高表达的组织样本通常也伴有BRG1高表达。此外，我们发现UCA1损害了BRG1与p21启动子的结合以及BRG1的染色质重塑活性。总的来说，这些结果表明UCA1通过抑制BRG1促进膀胱癌细胞增殖。
