Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction
Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction
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DOI：
10.1158/1078-0432.ccr-19-2230
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发表时间：
2020-04-01
影响因子：
11.5
通讯作者：
Honda, Hiroaki
中科院分区：
文献类型：
--
作者：
Kobatake, Kohei;Ikeda, Ken-ichiro;Honda, Hiroaki
目的：表观遗传失调与膀胱癌的发病机制密切相关。KDM 6A（赖氨酸（K）特异性脱甲基酶6A）是一种组蛋白修饰剂，在膀胱癌中经常发生突变。然而，KDM 6A缺乏如何促进膀胱癌发展的分子机制在很大程度上仍然未知。我们假设，澄清KDM 6A突变的膀胱癌的致病机制，可以帮助设计新的抗癌therapeutic.Experimental Design：我们产生的小鼠缺乏KDM 6a的尿路上皮细胞和交叉与小鼠杂合子的p53，其突变/缺失显着重叠的KDM 6A突变的肌肉浸润性膀胱癌（MIBC）。此外，BBN（N-丁基-N-（4-羟丁基）亚硝胺），一种香烟烟雾样诱变剂，被用作肿瘤促进剂。孤立的尿路上皮进行表型，病理，分子和细胞分析。我们的研究结果的临床相关性进一步分析使用患者的基因组和临床数据MIBC.Results：我们发现，Kdm 6a缺陷激活细胞因子和趋化因子途径，促进M2巨噬细胞极化，增加肿瘤干细胞，并导致膀胱癌的合作p53单倍不足。我们还发现，BBN治疗显著增强了促炎分子的表达，加速了疾病的发展。具有降低的KDM 6A表达的人膀胱癌样品也显示激活的促炎途径。值得注意的是，双重抑制IL 6和趋化因子（C-C基序）配体2，上调响应KDM 6A缺陷，有效地抑制KDM 6A缺陷的膀胱癌细胞growth.Conclusions：我们的研究结果提供了深入了解膀胱癌的多步骤致癌过程，并建议与KDM 6A功能障碍的膀胱癌患者的分子靶向治疗方法。
Purpose: Epigenetic deregulation is deeply implicated in the pathogenesis of bladder cancer. KDM6A (Lysine (K)-specific demethylase 6A) is a histone modifier frequently mutated in bladder cancer. However, the molecular mechanisms of how KDM6A deficiency contributes to bladder cancer development remains largely unknown. We hypothesized that clarification of the pathogenic mechanisms underlying KDM6A-mutated bladder cancer can help in designing new anticancer therapies.Experimental Design: We generated mice lacking Kdm6a in the urothelium and crossed them with mice heterozygous for p53, whose mutation/deletion significantly overlaps with the KDM6A mutation in muscle-invasive bladder cancer (MIBC). In addition, BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine), a cigarette smoke-like mutagen, was used as a tumor-promoting agent. Isolated urothelia were subjected to phenotypic, pathologic, molecular, and cellular analyses. The clinical relevance of our findings was further analyzed using genomic and clinical data of patients with MIBC.Results: We found that Kdm6a deficiency activated cytokine and chemokine pathways, promoted M2 macrophage polarization, increased cancer stem cells and caused bladder cancer in cooperation with p53 haploinsufficiency. We also found that BBN treatment significantly enhanced the expression of proinflammatory molecules and accelerated disease development. Human bladder cancer samples with decreased KDM6A expression also showed activated proinflammatory pathways. Notably, dual inhibition of IL6 and chemokine (C-C motif) ligand 2, upregulated in response to Kdm6a deficiency, efficiently suppressed Kdm6a-deficient bladder cancer cell growth.Conclusions: Our findings provide insights into multistep carcinogenic processes of bladder cancer and suggest molecular targeted therapeutic approaches for patients with bladder cancer with KDM6A dysfunction.