A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis
A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis
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由环状 SHPRH 基因编码的新型蛋白质可抑制神经胶质瘤的发生
DOI：
10.1038/s41388-017-0019-9
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发表时间：
2018-03-01
期刊：
影响因子：
8
通讯作者：
Zhang, Nu
中科院分区：
文献类型：
--
作者：
Zhang, Maolei;Huang, Nunu;Zhang, Nu
环状RNA（circRNA）是真核细胞中的功能性非编码转录物。近年来的研究表明，尽管circRNA的表达水平很低，但它们可能参与基因调控、组织发育和肿瘤发生等多种生理或病理过程。虽然“microRNA海绵”功能已得到很好的表征，但大多数circRNA不包含microRNA的完美捕获位点，这表明circRNA可能具有尚未定义的功能。在这项研究中，我们表明，一个circRNA含有一个开放的阅读框架（ORF）驱动的内部核糖体进入位点（IRES）可以翻译功能蛋白。SNF 2组蛋白接头PHD RING解旋酶（SHPRH）基因的环状形式编码一种新的蛋白质，我们称之为SHPRH-146 aa。环状SHPRH（circ-SHPRH）使用重叠的遗传密码产生一个“UGA”终止密码子，这导致17 kDa SHPRH-146 aa的翻译。circ-SHPRH和SHPRH-146 aa在正常人脑中大量表达，在胶质母细胞瘤中下调。SHPRH-146 aa在U251和U373胶质母细胞瘤细胞中的过表达降低了它们的恶性行为和体内体外致瘤性。SHPRH-146 aa在机制上保护全长SHPRH免受泛素蛋白酶体的降解。稳定的SHPRH作为E3连接酶依次泛素化增殖细胞核抗原（PCNA），导致抑制细胞增殖和致瘤性。我们的研究结果为circRNA在生理和病理过程中的功能提供了一个新的视角。具体而言，由circ-SHPRH的重叠遗传密码产生的SHPRH-146 aa是人胶质母细胞瘤中的肿瘤抑制因子。
Circular RNAs (circRNAs) are recognized as functional non-coding transcripts in eukaryotic cells. Recent evidence has indicated that even though circRNAs are generally expressed at low levels, they may be involved in many physiological or pathological processes, such as gene regulation, tissue development and carcinogenesis. Although the 'microRNA sponge' function is well characterized, most circRNAs do not contain perfect trapping sites for microRNAs, which suggests the possibility that circRNAs have functions that have not yet been defined. In this study, we show that a circRNA containing an open reading frame (ORF) driven by the internal ribosome entry site (IRES) can translate a functional protein. The circular form of the SNF2 histone linker PHD RING helicase (SHPRH) gene encodes a novel protein that we termed SHPRH-146aa. Circular SHPRH (circ-SHPRH) uses overlapping genetic codes to generate a 'UGA' stop codon, which results in the translation of the 17 kDa SHPRH-146aa. Both circ-SHPRH and SHPRH-146aa are abundantly expressed in normal human brains and are down-regulated in glioblastoma. The overexpression of SHPRH-146aa in U251 and U373 glioblastoma cells reduces their malignant behavior and tumorigenicity in vitro and in vivo. Mechanistically, SHPRH-146aa protects full-length SHPRH from degradation by the ubiquitin proteasome. Stabilized SHPRH sequentially ubiquitinates proliferating cell nuclear antigen (PCNA) as an E3 ligase, leading to inhibited cell proliferation and tumorigenicity. Our findings provide a novel perspective regarding circRNA function in physiological and pathological processes. Specifically, SHPRH-146aa generated from overlapping genetic codes of circ-SHPRH is a tumor suppressor in human glioblastoma.