The KMT1A-GATA3-STAT3 Circuit Is a Novel Self-Renewal Signaling of Human Bladder Cancer Stem Cells
The KMT1A-GATA3-STAT3 Circuit Is a Novel Self-Renewal Signaling of Human Bladder Cancer Stem Cells
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KMT1A-GATA3-STAT3 电路是人膀胱癌干细胞的一种新型自我更新信号
DOI：
10.1158/1078-0432.ccr-17-0882
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发表时间：
2017-11-01
影响因子：
11.5
通讯作者：
Wen, Tingyi
中科院分区：
文献类型：
--
作者：
Yang, Zhao;He, Luyun;Wen, Tingyi
目的：膀胱癌是世界范围内最常见的泌尿系恶性肿瘤之一，其特点是复发率高，且无针对性的治疗方法。膀胱癌干细胞(BCSCs)在肿瘤的发生、转移和耐药中起重要作用。然而，BCSCs的调控信号和自我更新机制在很大程度上仍不清楚。在这里，我们发现了一个新的信号，KMT1A-GATA3-STAT3电路，它促进了人BCSCs的自我更新和致瘤性。实验设计：采用转录组芯片技术对人膀胱癌干细胞、膀胱癌非干细胞(BCNSCs)、膀胱癌原代标本1、2以及膀胱癌细胞株EJ进行分析。在验证步骤中，应用10对膀胱癌和正常组织、不同的肿瘤细胞系、人类膀胱癌的公共微阵列数据集和癌症基因组图谱数据库来验证基因表达。结果：与BCNSCs和正常膀胱组织相比，KMT1a在BCSCs中高表达，并导致组蛋白H3(H3K9me3)修饰的三甲基化赖氨酸9的表达增加。GATA3结合在STAT3启动子的-1710∼-1530区域并抑制其转录。KMT1A介导的GATA3启动子-1351∼-1172BP区域的H3K9me3修饰抑制了GATA3的转录，上调了STAT3的表达。此外，激活的STAT3还触发了BCSCs的自我更新。此外，KMT1A或STAT3的缺失抑制了BCSC肿瘤微球和异种移植瘤的形成。结论：KMT1A通过KMT1A-GATA3-STAT3通路正向调节人BCSCs的自我更新和致瘤性，有望成为膀胱癌治疗的靶点。临床癌症资源；23(21)；6673-85。©2017 AACR。
Purpose: Bladder cancer is one of the most common urinary malignancies worldwide characterized by a high rate of recurrence and no targeted therapy method. Bladder cancer stem cells (BCSCs) play a crucial role in tumor initiation, metastasis, and drug resistance. However, the regulatory signaling and self-renewal mechanisms of BCSCs remain largely unknown. Here, we identified a novel signal, the KMT1A-GATA3-STAT3 circuit, which promoted the self-renewal and tumorigenicity of human BCSCs. Experimental Design: In a discovery step, human BCSCs and bladder cancer non-stem cells (BCNSCs) isolated from primary bladder cancer samples #1 and #2, and the bladder cancer cell line EJ were analyzed by transcriptome microarray. In a validation step, 10 paired bladder cancer and normal tissues, different tumor cell lines, the public microarray datasets of human bladder cancer, and The Cancer Genome Atlas database were applied for the verification of gene expression. Results: KMT1A was highly expressed and responsible for the increase of tri-methylating lysine 9 of histone H3 (H3K9me3) modification in BCSCs compared with either BCNSCs or normal bladder tissue. GATA3 bound to the -1710∼-1530 region of STAT3 promoter and repressed its transcription. H3K9me3 modification on the -1351∼-1172bp region of the GATA3 promoter mediated by KMT1A repressed the transcription of GATA3 and upregulated the expression of STAT3. In addition, the activated STAT3 triggered self-renewal of BCSCs. Furthermore, depletion of KMT1A or STAT3 abrogated the formation of BCSC tumorspheres and xenograft tumors. Conclusions: KMT1A positively regulated the self-renewal and tumorigenicity of human BCSCs via KMT1A-GATA3-STAT3 circuit, in which KMT1A could be a promising target for bladder cancer therapy. Clin Cancer Res; 23(21); 6673–85. ©2017 AACR.