Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2
Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2
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DOI：
10.1126/scitranslmed.aai8312
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发表时间：
2017-02-22
影响因子：
17.1
通讯作者：
Teh, Bin Tean
中科院分区：
文献类型：
--
作者：
Ler, Lian Dee;Ghosh, Sujoy;Teh, Bin Tean
含有KDM 6A的三叉神经样基团复合物与含有EZH 2的Polycomb-阻遏复合物2（PRC 2）在通过H3 K27甲基化维持基因表达的阻遏和激活的动力学方面具有拮抗作用。在尿路上皮膀胱癌中，KDM 6A（H3 K27脱甲基酶）经常发生突变，但其功能后果和治疗靶向性仍然未知。在这种癌症类型中，约70%的KDM 6A突变导致表达的完全丧失和随之而来的脱甲基酶功能的丧失。进一步的转录组分析发现，在KDM 6A突变的尿路上皮膀胱癌中存在多个失调的通路，尤其是PRC 2/EZH 2。染色质免疫沉淀测序分析揭示了H3 K27 me 3在KDM 6A缺失细胞中的特定位点处的富集，包括PRC 2/EZH 2及其下游靶标。因此，我们靶向EZH 2（一种H3 K27甲基化酶），并证明KDM 6A无效的膀胱尿路上皮癌细胞系对EZH 2抑制敏感。功能丧失和获得测定证实，KDM 6A丧失的细胞易受EZH 2的攻击。IGFBP 3是KDM 6A/EZH 2/H3 K27 me 3的直接靶点，通过EZH 2抑制而上调，并有助于在KDM 6A缺失细胞系中观察到的EZH 2依赖性生长抑制。EZH 2抑制延迟了KDM 6A无效细胞中的肿瘤发作，并在患者来源的和细胞系异种移植模型中引起KDM 6A无效膀胱肿瘤的消退。总之，我们的研究表明，KDM 6A的失活突变，这是常见的尿路上皮膀胱癌，是潜在的靶向抑制EZH 2。
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in KDM6A-mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in KDM6A-null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that KDM6A-null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss-and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/ EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in KDM6A-null cell lines. EZH2 inhibition delayed tumor onset in KDM6A-null cells and caused regression of KDM6A-null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of KDM6A, which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2.