Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development
Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development
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DOI：
10.1136/gutjnl-2013-306596
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发表时间：
2015-05-01
期刊：
影响因子：
24.5
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
--
作者：
Chia, Na-Yu;Deng, Niantao;Tan, Patrick
目的胃癌(GC)是一种致命的恶性肿瘤，需要新的治疗策略。三个转录因子，KLF5，GATA4和GATA6，已经被报道在GC中表现出基因组扩增。我们试图验证这些发现，研究这些因素如何促进GC，并确定携带这些扩增的GC的潜在治疗策略。设计：在多个GC队列中检查KLF5、GATA4和GATA6的拷贝数和基因表达。染色质免疫沉淀结合DNA测序鉴定胃癌细胞系中KLF5/GATA4/GATA6的基因组结合位点，并与转录组学结合以突出直接靶基因。结果KLF5、GATA4和GATA6扩增在独立的GC队列中得到证实。尽管因子扩增发生在不同的GCs组中，但它们在原代GCs中显示出显著的mRNA共表达，与KLF5/GATA4/GATA6的交叉调控一致。染色质免疫沉淀结合DNA测序发现，KLF5和GATA4/GATA6共占据了大量的基因组位点，主要位于基因启动子上，具有较高的结合强度。KLF5与GATA因子在物理上相互作用，支持KLF5/GATA4/GATA6对共占基因的协同调控。在体外和体内，这些因子的缺失和过度表达，无论是单独的还是联合的，分别减少和促进了癌症的增殖。在与肿瘤发生相关的KLF5/GATA4/GATA6直接靶基因中，有一个靶基因HNF4α也是GC增殖所必需的，并且可以被抗糖尿病药物二甲双胍靶向，这为KLF5/GATA4/GATA6扩增的GC提供了治疗机会。结论KLF5/GATA4/GATA6可能通过相互串扰，协同维持癌基因转录调控网络来促进GC的发展。
Objective Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications.Design KLF5, GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice.Results KLF5, GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4 alpha, was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs.Conclusions KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells.