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.
Highlights
Bladder cancer (BC) is a serious threat to public health and has one of the highest economically burdened tumor types worldwide (Leal et al, 2016; Wang H. et al, 2019)
The sorted Bladder cancer stem cells (BCSCs) were cultured in DMEM/F-12 medium supplemented with 20 ng/mL EGF, 20 ng/mL bFGF, 1% N2, and 2% B27, while bladder cancer non-stem cells (BCNSCs) were cultured in DMEM/F-12 medium supplemented with 15% FBS for 2–3 weeks until the number of cells was sufficient for Western blot (WB), generation of xenograft, chromatin immunoprecipitation (ChIP), and DNase I digestion experiments
Our previous study showed that histone methyltransferase KMT1A promoted self-renewal of BCSCs via the KMT1A– GATA3–STAT3 signaling pathway (Yang et al, 2017)
Summary
Bladder cancer (BC) is a serious threat to public health and has one of the highest economically burdened tumor types worldwide (Leal et al, 2016; Wang H. et al, 2019). BC has three major types, which are transitional cell carcinoma (TCC), squamous cell carcinoma, and adenocarcinoma, in which TCC comprises >90% of BC patients (Wu et al, 1998). Having distinct clinical characteristics and prognosis, BC is categorized into non-muscle invasive (NMI) and muscle invasive (MI; Kamat et al, 2016) types. The response rate of BC patients toward immune checkpoint inhibitors remained low (Rosenberg et al, 2016; Balar et al, 2017) and the recurrence rate of BC was high (Wu et al, 2016). It is of great importance to explore the mechanisms of BC tumorigenesis and novel therapeutic targets
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