Chaetocin Abrogates the Self-Renewal of Bladder Cancer Stem Cells <i>via</i> the Suppression of KMT1A-GATA3-STAT3 Circuit

Abstract

Background: Bladder cancer stem cells (BCSCs) have the abilities of self-renewal, differentiation, metastasis, conferring drug resistance and exhibiting high tumorigenicity. KMT1A-GATA3-STAT3 axis was proved to maintain the stemness of BCSCs, in which KMT1A was highly expressed in BCSCs rather than bladder cancer non-stem cells (BCNSCs) and normal bladder epithelial cells. However, the therapeutic effect of targeting KMT1A in bladder cancer (BC) or BCSCs remains unknown. Methods: In this study, we confirmed that the expression of KMT1A was remarkably higher in BCSCs than those in BCNSCs. Six histone methyltransferase inhibitors AMI-1, BIX-01294, chaetocin, DZNeP, GSK343 and UNC0631 were investigated targeting KMT1A through cell proliferation assay. Findings: Among those, chaetocin suppressed the cell propagation, induced apoptosis and caused G1 phase cell cycle arrest of BC cells, without influencing normal bladder epithelial cells. More importantly, chaetocin abrogated the self-renewal of BCSCs via the suppression of KMT1A-GATA3-STAT3 circuit and other stemness-related pathways. Finally, intravesical instillation of chaetocin inhibited the formation of BCSCs tumor spheres and xenograft tumors. Chaetocin is an effective histone methyltransferase inhibitor targeting KMT1A in BCSCs. Furthermore, chaetocin abrogated the stemness maintenance and tumor growth of BCSCs via the suppression of KMT1A-GATA3-STAT3 circuit. In future, chaetocin can be a potential therapeutic strategy for BC. Funding Statement: This work was supported by the Basic Scientific Research Operating Expenses for Central Universities (No. buctrc201910), National Natural Science Foundation of China (81602644), the project of Basic Research Cooperation of Beijing-Tianjin-Hebei (H2019104018) and the grant from the Ministry of Science and Technology of China (2010ZX09401-403). Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: Human tissues were obtained from The Second Affiliated Hospital of Kunming Medical University College (Kunming, China) with informed consent and approved by the Research Ethics Board at The Second Affiliated Hospital of Kunming Medical University. The mice were maintained under standard conditions according to the institutional guidelines for animal care. All animal experiments were approved by the Animal Ethics Committee of The Second Affiliated Hospital of Kunming Medical University College (Kunming, China) and were carried out in compliance with the Animal Management Rules of the Ministry of Health of the People's Republic of China.