LBPO.MCB02 · 分子与细胞生物学 · Late-Breaking
KDM4A介导的染色质重塑促进恶性胸膜间皮瘤的肿瘤进展和免疫调节
KDM4A mediated chromatin remodeling promotes tumor progression and immune modulation in malignant pleural mesothelioma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
恶性胸膜间皮瘤（MPM）是一种罕见、侵袭性的癌症，累及肺部的胸膜衬里。SETD2在一部分MPM患者中发生突变，并导致对KDM4A的依赖性。初步研究揭示，KDM4A的过表达在MPM细胞系和患者样本中也高度表达。此外，TCGA数据分析提示，与其他癌症类型相比，MPM具有最高的相对KDM4A表达。KDM4A即赖氨酸组蛋白去甲基化酶4A，调节H3K36me3和H3K9me3的去甲基化，已知在癌症发展中调控凋亡、DNA修复、剪接、自我更新及其他生物学过程。然而，KDM4A在MPM中的作用尚未完全明确。在本研究中，我们旨在界定KDM4A在MPM中的作用。下调KDM4A后的转录组分析导致固有免疫反应基因表达的重新激活，包括干扰素γ刺激基因（ISG's），以及WNT通路靶基因表达的抑制，提示KDM4A与WNT信号通路之间存在串扰。我们还观察到参与DNA修复的基因表达下降，包括同源重组（HR）、错配修复和碱基切除修复（BER）机制。KDM4A与WNT通路的双重抑制在MPM细胞系中表现出协同作用。染色质免疫沉淀测序（ChIP-seq）显示，正如预期，敲低KDM4A后多个KDM4A靶基因（包括DNA修复基因和WNT靶基因）上H3K9me3的沉积增加。使用KDM4A特异性抑制剂处理导致细胞死亡并调控WNT通路靶基因，提示将KDM4A靶向治疗与WNT靶向抑制剂和/或CHK1/2抑制剂联合使用可能使MPM患者获益。抑制KDM4A在患者来源异种移植中导致肿瘤生长减少。因此，靶向KDM4A为预后不良的MPM患者的治疗方法开辟了新途径，并有可能提高生存率。
查看英文原文 English abstract
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer affecting the pleural lining of the lungs. SETD2 is mutated in a subset of MPM patients and result in dependency on KDM4A . Preliminary studies revealed overexpression of KDM4A is also highly expressed in MPM cell lines and patient samples. Furthermore, TCGA data analysis suggested that MPM has the highest relative KDM4A expression compared to other cancer types. KDM4A , lysine histone demethylase 4A, regulates demethylation of H3K36me3 and H3K9me3 and, known to regulate apoptosis, DNA repair, splicing, self-renewal and other biological processes in cancer development. However, the role of KDM4A in MPM is not fully understood. In the present study, we aimed to define the role of KDMA4 in MPM. Transcriptomic analysis following the down regulation of KDM4A resulted in reactivation of innate immune response gene expression including the interferon gamma stimulatory genes (ISG's), and inhibition of WNT pathway target gene expression suggesting a crosstalk between KDM4A and WNT signaling pathway. We also observed a decrease in expression of genes involved in DNA repair including HR, mismatch and BER mechanisms. Dual inhibition of KDM4A and WNT pathway exhibited synergy in MPM cell lines. Chromatin Immunoprecipitation-seq (ChIP-seq) revealed increased deposition of H3K9me3 on multiple KDM4A target genes as expected including the DNA repair genes and WNT target genes upon knockdown of KDM4A. Treatment with KDM4A specific inhibitors resulted in cell death and regulated WNT pathway target genes, suggesting that combining KDM4A-targeted therapy with WNT targeting inhibitors and/or CHK1/2 inhibitors could potentially benefit MPM patients. Inhibition of KDM4A resulted in decreased tumor growth in patient derived xenografts. Thus, targeting KDM4A opens new avenues for therapeutic approaches in MPM patients with poor prognosis and potentially increase survival.
利益披露 Disclosure
S. Saladi, None..
H. Vemula, None..
M. Sattler, None.