CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification
CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification
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DOI：
10.1186/s12943-020-01160-2
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发表时间：
2020-03-12
期刊：
影响因子：
37.3
通讯作者：
Yang, Shiming
中科院分区：
文献类型：
--
作者：
Jie, Mengmeng;Wu, Yaran;Yang, Shiming
背景 环状RNA的异常表达有助于癌症的发生和进展，但其潜在机制仍然难以捉摸。方法采用RNA-seq和qRT-PCR筛选胃癌组织与癌旁正常组织差异表达的circRNA。筛选出候选 circRNA (circMRPS35)，并通过 qRT-PCR 进行验证。通过CCK-8和细胞侵袭实验测定细胞增殖和侵袭能力。进一步应用RNA-seq、GO-pathway、RNA pull-down和ChIRP来寻找详细机制。结果通过RNA-seq在胃癌组织中筛选出一种新的circRNA，命名为circMRPS35，其表达与胃癌患者的临床病理特征和预后相关。从生物学角度来看，circMRPS35在体外和体内抑制胃癌细胞的增殖和侵袭。从机制上讲，circMRPS35充当模块化支架，将组蛋白乙酰转移酶KAT7招募到FOXO1和FOXO3a基因的启动子上，从而引发其启动子中的H4K5乙酰化。特别地，circMRPS35直接特异性结合FOXO1/3a启动子区域。因此，它显着激活FOXO1/3a的转录并触发其下游靶基因表达的后续反应，包括p21、p27、Twist1和E-cadherin，从而抑制细胞增殖和侵袭。此外，胃癌组织中circMRPS35的表达与FOXO1/3a的表达呈正相关。结论 我们的研究结果不仅揭示了 circMRPS35 在抗癌治疗中控制组蛋白修饰的关键作用，而且主张触发 circMRPS35/KAT7/FOXO1/3a 通路来对抗胃癌。
Background Aberrant expression of circular RNAs contributes to the initiation and progression of cancers, but the underlying mechanism remains elusive. Methods RNA-seq and qRT-PCR were performed to screen differential expressed circRNAs between gastric cancer tissues and adjacent normal tissues. Candidate circRNA (circMRPS35) was screened out and validated by qRT-PCR. Cell proliferation and invasion ability were determined by CCK-8 and cell invasion assays. RNA-seq, GO-pathway, RNA pull-down and ChIRP were further applied to search for detailed mechanism. Results Here, a novel circRNA named circMRPS35, was screened out by RNA-seq in gastric cancer tissues, whose expression is related to clinicopathological characteristics and prognosis in gastric cancer patients. Biologically, circMRPS35 suppresses the proliferation and invasion of gastric cancer cells in vitro and in vivo. Mechanistically, circMRPS35 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of FOXO1 and FOXO3a genes, which elicits acetylation of H4K5 in their promoters. Particularly, circMRPS35 specifically binds to FOXO1/3a promoter regions directly. Thus, it dramatically activates the transcription of FOXO1/3a and triggers subsequent response of their downstream target genes expression, including p21, p27, Twist1 and E-cadherin, resulting in the inhibition of cell proliferation and invasion. Moreover, circMRPS35 expression positively correlates with that of FOXO1/3a in gastric cancer tissues. Conclusions Our findings not only reveal the pivotal roles of circMRPS35 in governing histone modification in anticancer treatment, but also advocate for triggering circMRPS35/KAT7/FOXO1/3a pathway to combat gastric cancer.