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Chaetocin Abrogates the Self-Renewal of Bladder Cancer Stem Cells via the Suppression of the KMT1A–GATA3–STAT3 Circuit(Open Access)

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机构： [1]College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China [2]Department of Urology, Second Affiliated Hospital of Kunming Medical University, Kunming, China [3]Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China [4]Department of Urology, Affiliated Hospital of Hebei University, Baoding, China [5]Department of Pathogenobiology, College of Basic Medical Science, Jilin University, Changchun, China [6]Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

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关键词： bladder cancer bladder cancer stem cells chaetocin KMT1A target therapy

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Bladder cancer stem cells (BCSCs) have the abilities of self-renewal, differentiation, and metastasis; confer drug resistance; and exhibit high tumorigenicity. We previously identified that the KMT1A–GATA3–STAT3 axis drives the self-renewal of BCSCs. However, the therapeutic effect of targeting KMT1A in BCSCs remains unknown. In this study, we confirmed that the expression of KMT1A was remarkably higher in BCSCs (3–5-fold) than those in bladder cancer non-stem cells or normal bladder epithelial cells. Among the six KMT1A inhibitors, chaetocin significantly suppressed the cell propagation (inhibition ratio: 65%–88%, IC50 = 24.4–32.5 nM), induced apoptosis (2–5-fold), and caused G1 phase cell cycle arrest (68.9 vs 55.5%) of bladder cancer (BC) cells, without influencing normal bladder epithelial cells. More importantly, chaetocin abrogated the self-renewal of BCSCs (inhibition ratio: 80.1%) via the suppression of the KMT1A–GATA3–STAT3 circuit and other stemness-related pathways. Finally, intravesical instillation of chaetocin remarkably inhibited the growth of xenograft tumors (inhibition ratio: 71–82%) and prolonged the survival of tumor-bearing mice (70 vs 53 days). In sum, chaetocin abrogated the stemness maintenance and tumor growth of BCSCs via the suppression of the KMT1A–GATA3–STAT3 circuit. Chaetocin is an effective inhibitor targeting KMT1A in BCSCs and could be a promising therapeutic strategy for BC. © Copyright © 2020 Yang, Wang, Zhang, Xing, Zhang, Wang, Li and Yu.

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出版当年[2019]版：

大类 | 2 区生物

小类 | 2 区发育生物学 3 区细胞生物学

最新[2025]版：

大类 | 2 区生物学

小类 | 2 区发育生物学 3 区细胞生物学

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出版当年[2018]版：

Q1 DEVELOPMENTAL BIOLOGY Q1 CELL BIOLOGY

最新[2023]版：

Q1 DEVELOPMENTAL BIOLOGY Q2 CELL BIOLOGY

影响因子： 4.6 最新[2023版] 5.2 最新五年平均 5.206 出版当年[2018版] 0 出版当年五年平均 0 出版前一年[2017版] 5.186 出版后一年[2019版]

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第一作者机构： [1]College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China

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