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CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification
Molecular Cancer ( IF 27.7 ) Pub Date : 2020-03-12 , DOI: 10.1186/s12943-020-01160-2
Mengmeng Jie , Yaran Wu , Mengyuan Gao , Xinzhe Li , Cheng Liu , Qin Ouyang , Qingyun Tang , Changyu Shan , Yangfan Lv , Kebin Zhang , Qian Dai , Yang Chen , Shuo Zeng , Chenglin Li , Liting Wang , Fengtian He , Changjiang Hu , Shiming Yang

Aberrant expression of circular RNAs contributes to the initiation and progression of cancers, but the underlying mechanism remains elusive. 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. 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. 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.

中文翻译:

CircMRPS35通过募集KAT7来控制组蛋白修饰来抑制胃癌的进展

环状RNA的异常表达有助于癌症的发生和发展,但潜在的机制仍然难以捉摸。进行RNA-seq和qRT-PCR来筛选胃癌组织和邻近正常组织之间差异表达的circRNA。筛选出候选circRNA(circMRPS35),并通过qRT-PCR进行验证。细胞增殖和侵袭能力通过CCK-8和细胞侵袭测定法确定。RNA-seq,GO途径,RNA下拉和ChIRP进一步用于寻找详细的机制。在这里,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有关。在生物学上,circMRPS35在体外和体内抑制胃癌细胞的增殖和侵袭。在机制上,circMRPS35充当模块支架,将组蛋白乙酰转移酶KAT7募集到FOXO1和FOXO3a基因的启动子,后者在其启动子中引发H4K5的乙酰化。特别地,circMRPS35直接与FOXO1 / 3a启动子区域特异性结合。因此,它极大地激活了FOXO1 / 3a的转录并触发了其下游靶基因表达的后续响应,包括p21,p27,Twist1和E-cadherin,从而抑制了细胞的增殖和侵袭。此外,circMRPS35表达与胃癌组织中FOXO1 / 3a的表达呈正相关。我们的发现不仅揭示了circMRPS35在控制抗癌治疗中组蛋白修饰中的关键作用,而且还倡导触发circMRPS35 / KAT7 / FOXO1 / 3a途径来对抗胃癌。circMRPS35充当模块支架,将组蛋白乙酰转移酶KAT7募集到FOXO1和FOXO3a基因的启动子,后者在其启动子中引发H4K5的乙酰化。特别地,circMRPS35直接与FOXO1 / 3a启动子区域特异性结合。因此,它极大地激活了FOXO1 / 3a的转录并触发了其下游靶基因表达的后续响应,包括p21,p27,Twist1和E-cadherin,从而抑制了细胞的增殖和侵袭。此外,circMRPS35表达与胃癌组织中FOXO1 / 3a的表达呈正相关。我们的发现不仅揭示了circMRPS35在控制抗癌治疗中组蛋白修饰中的关键作用,而且还倡导触发circMRPS35 / KAT7 / FOXO1 / 3a途径来对抗胃癌。circMRPS35充当模块支架,将组蛋白乙酰转移酶KAT7募集到FOXO1和FOXO3a基因的启动子,后者在其启动子中引发H4K5的乙酰化。特别地,circMRPS35直接与FOXO1 / 3a启动子区域特异性结合。因此,它极大地激活了FOXO1 / 3a的转录并触发了其下游靶基因表达的后续响应,包括p21,p27,Twist1和E-cadherin,从而抑制了细胞的增殖和侵袭。此外,circMRPS35表达与胃癌组织中FOXO1 / 3a的表达呈正相关。我们的发现不仅揭示了circMRPS35在控制抗癌治疗中组蛋白修饰中的关键作用,而且还倡导触发circMRPS35 / KAT7 / FOXO1 / 3a途径来对抗胃癌。
更新日期:2020-04-22
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