CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Clin Cancer Res. 2017 Nov 1;23(21):6673-6685. doi: 10.1158/1078-0432.CCR-17-0882. Epub 2017 Aug 1.
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. 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. 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 promoter and repressed its transcription. H3K9me3 modification on the -1351∼-1172bp region of the promoter mediated by KMT1A repressed the transcription of and upregulated the expression of STAT3. In addition, the activated STAT3 triggered self-renewal of BCSCs. Furthermore, depletion of or abrogated the formation of BCSC tumorspheres and xenograft tumors. 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. .
膀胱癌是全球最常见的泌尿系统恶性肿瘤之一，其特点是复发率高，且无靶向治疗方法。膀胱癌干细胞（BCSCs）在肿瘤起始、转移和耐药中起关键作用。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，我们鉴定了一个新的信号，即 KMT1A-GATA3-STAT3 通路，它促进了人 BCSCs 的自我更新和致瘤性。在发现步骤中，我们通过转录组微阵列分析了从原发性膀胱癌样本 #1 和 #2 中分离的人 BCSCs 和膀胱癌非干细胞（BCNSCs）以及膀胱癌细胞系 EJ。在验证步骤中，我们应用 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。与 BCNSCs 或正常膀胱组织相比，KMT1A 在 BCSCs 中高度表达，并负责增加组蛋白 H3 赖氨酸 9 的三甲基化（H3K9me3）修饰。GATA3 结合到 启动子的-1710∼-1530 区域，并抑制其转录。KMT1A 介导的 启动子-1351∼-1172bp 区域的 H3K9me3 修饰抑制了 的转录，并上调了 STAT3 的表达。此外，激活的 STAT3 触发了 BCSC 的自我更新。此外，耗尽 或 会破坏 BCSC 肿瘤球和异种移植肿瘤的形成。KMT1A 通过 KMT1A-GATA3-STAT3 通路正向调节人 BCSC 的自我更新和致瘤性，其中 KMT1A 可能成为膀胱癌治疗的有希望的靶点。
