Yang Zhao, Wang Haifeng, Zhang Nan, Xing Tianying, Zhang Wei, Wang Guoqing, Li Chong, Yu Changyuan
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
Department of Urology, Second Affiliated Hospital of Kunming Medical University, Kunming, China.
Front Cell Dev Biol. 2020 Jun 17;8:424. doi: 10.3389/fcell.2020.00424. eCollection 2020.
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%, IC = 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.
膀胱癌干细胞（BCSCs）具有自我更新、分化和转移能力；赋予耐药性；并表现出高致瘤性。我们先前已确定KMT1A-GATA3-STAT3轴驱动BCSCs的自我更新。然而，靶向KMT1A对BCSCs的治疗效果仍不清楚。在本研究中，我们证实KMT1A在BCSCs中的表达显著高于膀胱癌非干细胞或正常膀胱上皮细胞（3-5倍）。在六种KMT1A抑制剂中，毛壳素显著抑制膀胱癌细胞的细胞增殖（抑制率：65%-88%，IC = 24.4-32.5 nM），诱导细胞凋亡（2-5倍），并导致G1期细胞周期阻滞（68.9%对55.5%），而不影响正常膀胱上皮细胞。更重要的是，毛壳素通过抑制KMT1A-GATA3-STAT3回路和其他干性相关途径消除了BCSCs的自我更新（抑制率：80.1%）。最后，膀胱内灌注毛壳素显著抑制异种移植肿瘤的生长（抑制率：71-82%），并延长荷瘤小鼠的生存期（70天对53天）。总之，毛壳素通过抑制KMT1A-GATA3-STAT3回路消除了BCSCs的干性维持和肿瘤生长。毛壳素是一种靶向BCSCs中KMT1A的有效抑制剂，可能是一种有前途的膀胱癌治疗策略。
