Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing, 400038, China.
Mol Cancer. 2020 Mar 12;19(1):56. doi: 10.1186/s12943-020-01160-2.
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.
环状 RNA 的异常表达有助于癌症的发生和发展，但潜在机制仍难以捉摸。
通过 RNA-seq 和 qRT-PCR 筛选胃癌组织和相邻正常组织之间差异表达的 circRNAs。通过 qRT-PCR 筛选出候选 circRNA（circMRPS35）并进行验证。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 通路、RNA 下拉和 ChIRP 寻找详细的机制。
在此，通过 RNA-seq 在胃癌组织中筛选出一种新型环状 RNA，命名为 circMRPS35，其表达与胃癌患者的临床病理特征和预后相关。在生物学上，circMRPS35 抑制胃癌细胞在体外和体内的增殖和侵袭。机制上，circMRPS35 作为模块化支架，将组蛋白乙酰转移酶 KAT7 募集到 FOXO1 和 FOXO3a 基因的启动子上，导致其启动子上 H4K5 的乙酰化。特别是，circMRPS35 可以特异性地结合 FOXO1/3a 启动子区域。因此，它显著激活 FOXO1/3a 的转录，并引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，circMRPS35 的表达与胃癌组织中 FOXO1/3a 的表达呈正相关。
我们的研究结果不仅揭示了 circMRPS35 在抗癌治疗中调控组蛋白修饰的关键作用，还提倡触发 circMRPS35/KAT7/FOXO1/3a 通路来治疗胃癌。
