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  • Title: Chaetocin Abrogates the Self-Renewal of Bladder Cancer Stem Cells via the Suppression of the KMT1A-GATA3-STAT3 Circuit.
    Author: Yang Z, Wang H, Zhang N, Xing T, Zhang W, Wang G, Li C, Yu C.
    Journal: Front Cell Dev Biol; 2020; 8():424. PubMed ID: 32626701.
    Abstract:
    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.
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