Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA.
Oncogene. 2020 Oct;39(40):6265-6285. doi: 10.1038/s41388-019-0902-7. Epub 2019 Aug 5.
Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures. Here, we show that distinct, stage-wise metabolic alterations in BLCA are associated with the loss of function of aldehyde oxidase (AOX1). AOX1 associated metabolites have a high predictive value for advanced BLCA and our findings demonstrate that AOX1 is epigenetically silenced during BLCA progression by the methyltransferase activity of EZH2. Knockdown (KD) of AOX1 in normal bladder epithelial cells re-wires the tryptophan-kynurenine pathway resulting in elevated NADP levels which may increase metabolic flux through the pentose phosphate (PPP) pathway, enabling increased nucleotide synthesis, and promoting cell invasion. Inhibition of NADP synthesis rescues the metabolic effects of AOX1 KD. Ectopic AOX1 expression decreases NADP production, PPP flux and nucleotide synthesis, while decreasing invasion in cell line models and suppressing growth in tumor xenografts. Further gain and loss of AOX1 confirm the EZH2-dependent activation, metabolic deregulation, and tumor growth in BLCA. Our findings highlight the therapeutic potential of AOX1 and provide a basis for the development of prognostic markers for advanced BLCA.
高级膀胱癌（BLCA）仍然是一个临床挑战，缺乏有效的治疗措施。在这里，我们表明，BLCA 中不同阶段的代谢改变与醛氧化酶（AOX1）功能丧失有关。与 AOX1 相关的代谢物对晚期 BLCA 具有很高的预测价值，我们的研究结果表明，在 BLCA 进展过程中，EZH2 的甲基转移酶活性使 AOX1 发生表观遗传沉默。在正常膀胱上皮细胞中敲低（KD）AOX1 会重新连接色氨酸-犬尿氨酸途径，导致 NADP 水平升高，这可能会增加戊糖磷酸（PPP）途径的代谢通量，从而促进核苷酸合成，并促进细胞侵袭。抑制 NADP 合成可挽救 AOX1 KD 的代谢效应。异位 AOX1 表达降低 NADP 生成、PPP 通量和核苷酸合成，同时降低细胞系模型中的侵袭，并抑制肿瘤异种移植物的生长。进一步获得和丧失 AOX1 证实了 EZH2 依赖性激活、代谢失调和 BLCA 中的肿瘤生长。我们的研究结果强调了 AOX1 的治疗潜力，并为开发晚期 BLCA 的预后标志物提供了依据。
