Yang Han-Jie, Liu Tian, Xiong Yang
Department of Urology, Pingxiang Affiliated Hospital, Southern Medical University, 337000, Pingxiang, P. R. China.
Cell Death Discov. 2022 May 3;8(1):242. doi: 10.1038/s41420-022-00956-z.
Accumulating evidence has highlighted the important roles of long intergenic non-coding RNAs (lincRNAs) during cancer progression. However, the involvement of LINC00478 in bladder cancer remains largely unclear. Accordingly, the current study sought to investigate the function of LINC00478 on malignant phenotypes of bladder cancer cells as well as the underlying mechanism. By integrating data from in silico analysis, we uncovered that LINC00478 was differentially expressed in bladder cancer. We further analyzed the expression of LINC00478 and matrix metalloprotein 9 (MMP9) in bladder cancer tissues and cell lines and observed a significant decline in LINC00478 expression and an elevation in MMP9 expression. In addition, chromatin immunoprecipitation, RNA-binding protein immunoprecipitation, and RNA pull-down assays predicted and validated that LINC00478 targeted lysine-specific demethylase-1 (KDM1A) and down-regulated the expression of MMP9 by decreasing the monomethylation on lysine 4 of histone H3 (H3K4me1) of MMP9 promoter. Treatment with KDM1A inhibitor tranylcypromine (TCP) also led to an increase in the enrichment of H3K4me1 in the MMP9 promoter region. Through gain- and loss-of-function approaches, we found that LINC00478 up-regulation diminished the malignant phenotype of bladder cancer cells in vitro, and further inhibited xenograft tumor growth and metastasis in vivo by repressing MMP9. Collectively, our findings unraveled a LINC00478-mediated inhibitory mechanism in bladder cancer via the recruitment of histone demethylation transferase KDM1A to the MMP9 promoter region, which can provide potential implications for novel therapeutic targets against bladder cancer.
越来越多的证据表明长链基因间非编码RNA（lincRNAs）在癌症进展过程中发挥着重要作用。然而，LINC00478在膀胱癌中的作用仍不清楚。因此，本研究旨在探讨LINC00478对膀胱癌细胞恶性表型的影响及其潜在机制。通过整合计算机分析数据，我们发现LINC00478在膀胱癌中存在差异表达。我们进一步分析了LINC00478和基质金属蛋白酶9（MMP9）在膀胱癌组织和细胞系中的表达，发现LINC00478表达显著下降，而MMP9表达升高。此外，染色质免疫沉淀、RNA结合蛋白免疫沉淀和RNA下拉实验预测并验证了LINC00478靶向赖氨酸特异性去甲基化酶-1（KDM1A），并通过减少MMP9启动子组蛋白H3第4位赖氨酸（H3K4me1）的单甲基化来下调MMP9的表达。用KDM1A抑制剂反苯环丙胺（TCP）处理也导致MMP9启动子区域H3K4me1的富集增加。通过功能获得和功能缺失方法，我们发现上调LINC00478可在体外减弱膀胱癌细胞的恶性表型，并通过抑制MMP9进一步抑制体内异种移植肿瘤的生长和转移。总的来说，我们的研究结果揭示了LINC00478通过招募组蛋白去甲基化转移酶KDM1A到MMP9启动子区域介导的膀胱癌抑制机制，这可为膀胱癌的新治疗靶点提供潜在的启示。
