circEZH2(E2) (/E3) is a dual suppressor of miR363/miR708 to promote EZH2 expression and prostate cancer progression.
circEZH2(E2) (/E3) is a dual suppressor of miR363/miR708 to promote EZH2 expression and prostate cancer progression.
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circEZH2E2/E3 是 miR363/miR708 的双重抑制因子，可促进 EZH2 表达和前列腺癌进展
作者：
组蛋白甲基转移酶增强子zeste同源物2（EZH 2）在包括前列腺癌（PCa）在内的多种恶性肿瘤中过表达，并且可能在肿瘤进展中起重要作用。据报道，基因拷贝数增加、转录增强和一些circRNA上调EZH 2。目前尚不清楚EZH 2本身是否会产生促进自身表达的circRNA。我们在此报告了来源于EZH 2基因外显子2和3的circEZH 2 E2/E3的鉴定，并在PCa中过表达。我们发现circEZH 2 E2/E3作为miR 363和miR 708的双重抑制剂发挥作用，miR 363和miR 708分别靶向EZH 2 3′UTR和CDS，导致EZH 2表达上调，因此下调EZH 2抑制基因（例如，CDH 1和DAB 2 IP），以及PCa细胞增殖、迁移、侵袭和异种移植物PCa生长的增强。circEZH 2 E2/E3的过表达与PCa患者中较高的肿瘤分级、肿瘤进展以及不利的无进展和疾病特异性生存期显著相关。这些发现显示了一种新的自增强EZH 2-circEZH 2 E2/E3-miR 363/miR 708-EZH 2调节环，其中circEZH 2 E2/E3通过上调EZH 2在PCa肿瘤发生和进展中起重要作用，并且可能在PCa管理中具有潜在的诊断，预后和治疗用途。EZH 2衍生的circEZH 2 E2/E3作为miR 363和miR 708的双重抑制因子，通过竞争性结合miRNA并阻断其对EZH 2表达的抑制作用，导致EZH 2过表达，从而抑制下游肿瘤抑制基因如E-钙粘蛋白和DAB 2 IP的转录，促进前列腺癌细胞生长和肿瘤进展。
The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is overexpressed in a variety of malignancies including prostate cancer (PCa) and may play important roles in tumor progression. Gene copy number gains, enhanced transcription, and a few circRNAs have been reported to upregulate EZH2. It was not known whether EZH2 itself generates circRNAs that promote its own expression. We here report the identification of circEZH2E2/E3 that is derived from exons 2 and 3 of the EZH2 gene and overexpressed in PCa. We show that circEZH2E2/E3 functions as a dual inhibitor for both miR363 and miR708 that target the EZH2 3′UTR and CDS, respectively, resulting in the upregulation of EZH2 expression and hence the downregulation of EZH2‐repressed genes (e.g., CDH1 and DAB2IP), and enhancement of PCa cell proliferation, migration, invasion, and xenograft PCa growth. Overexpression of circEZH2E2/E3 is significantly correlated with higher tumor grade, tumor progression, and unfavorable progression‐free and disease‐specific survival in PCa patients. These findings show a novel autoenhancing EZH2–circEZH2E2/E3‐miR363/miR708–EZH2 regulatory loop, by which circEZH2E2/E3 plays important roles in PCa tumorigenesis and progression by upregulating EZH2, and may have potential diagnostic, prognostic, and therapeutic uses in PCa management. The EZH2‐derived circEZH2E2/E3 functions as a dual suppressor of both miR363 and miR708 by competitively binding to miRNAs and blocking their inhibitory effects on EZH2 expression, resulting in EZH2 overexpression, which in turn inhibits transcription of downstream tumor‐suppressive genes such as E‐cadherin and DAB2IP and promotes prostate cancer cell growth and tumor progression.
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影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
16
作者：
Lee, Shuet Theng;Li, Zhimei;Yu, Qiang
通讯作者：
Yu, Qiang
circ-Sirt1 通过序列特异性相互作用控制 NF-B 激活，并通过与血管平滑肌细胞中的 miR-132/212 结合增强 SIRT1 表达
影响因子：
14.9
作者：
Kong, Peng;Yu, Yuan;Han, Mei
通讯作者：
Han, Mei
影响因子：
3.5
作者：
Gao, Fengquan;Du, Yan;Chen, Dagang
通讯作者：
Chen, Dagang
DOI：
10.1038/s41573-020-00108-x
发表时间：
2021-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Bhat KP;Ümit Kaniskan H;Jin J;Gozani O
通讯作者：
Gozani O