机构：[1]CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.[2]Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.[3]CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.[4]Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.[5]Beijing Jianlan Institute of Medicine, Beijing, China.[6]Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
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 similar to-1530 region of STAT3 promoter and repressed its transcription. H3K9me3 modification on the -1351 similar to-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. (C) 2017 AACR.
基金：
This work was supported by the National Natural Science Foundation of
China (81602644 to Z. Yang, 81672956 to C. Li, 81472413 to C. Li) and the
grant from the Ministry of Science and Technology of China (2010ZX09401-
403 to T. Wen).
第一作者机构：[1]CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
通讯作者：
通讯机构：[*1]Institute of Microbiology, 1 West Beichen Road, Chaoyang District, Beijing 100101, China.[*2]Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
推荐引用方式(GB/T 7714)：
Zhao Yang,Luyun He,Kaisu Lin,et al.The KMT1A-GATA3-STAT3 Circuit Is a Novel Self-Renewal Signaling of Human Bladder Cancer Stem Cells[J].CLINICAL CANCER RESEARCH.2017,23(21):6673-6685.doi:10.1158/1078-0432.CCR-17-0882.
APA：
Zhao Yang,Luyun He,Kaisu Lin,Yun Zhang,Aihua Deng...&Tingyi Wen.(2017).The KMT1A-GATA3-STAT3 Circuit Is a Novel Self-Renewal Signaling of Human Bladder Cancer Stem Cells.CLINICAL CANCER RESEARCH,23,(21)
MLA：
Zhao Yang,et al."The KMT1A-GATA3-STAT3 Circuit Is a Novel Self-Renewal Signaling of Human Bladder Cancer Stem Cells".CLINICAL CANCER RESEARCH 23..21(2017):6673-6685
医学