A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity.
A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity.
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由环状 SMO RNA 编码的新型蛋白质对于 Hedgehog 信号传导激活和胶质母细胞瘤致瘤性至关重要。
DOI：
10.1186/s13059-020-02250-6
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发表时间：
2021-01-14
期刊：
影响因子：
12.3
通讯作者：
Zhang N
中科院分区：
文献类型：
--
作者：
Wu X;Xiao S;Zhang M;Yang L;Zhong J;Li B;Li F;Xia X;Li X;Zhou H;Liu D;Huang N;Yang X;Xiao F;Zhang N
Hedgehog通路的异常激活驱动许多癌症的肿瘤发生，包括胶质母细胞瘤。然而，G蛋白偶联样受体smoothened（SMO）的致敏机制，刺猬信号的关键组成部分，仍然在很大程度上是未知的。在这项研究中，我们描述了一个新的蛋白质SMO-193a.a。这是胶质母细胞瘤中Hedgehog信号激活所必需的。编码为圆形SMO（circ-SMO），SMO-193 a. a.通过与SMO相互作用，增强SMO胆固醇修饰，以及从补丁跨膜受体的抑制中释放SMO，是音刺猬（Shh）诱导的SMO激活所必需的。SMO-193a.a.在脑癌干细胞中，Hedgehog信号强度减弱并抑制自我更新、体外增殖和体内致瘤性。此外，circ-SMO/SMO-193 a. a.受Gli 1的直接转录靶点FUS的正调控。Shh/Gli1/FUS/SMO-193a.a.形成正反馈回路以维持胶质母细胞瘤中的Hedgehog信号激活。临床上，SMO-193a.a.在胶质母细胞瘤中比SMO更特异性地表达，并且与Gli 1表达相关。SMO-193a. a.预测胶质母细胞瘤患者的总体生存率较差，表明其预后价值。我们的研究表明，SMO-193a.a.，一种由环状SMO编码的新蛋白，对Hedgehog信号传导至关重要，驱动胶质母细胞瘤肿瘤发生，是胶质母细胞瘤治疗的新靶点。
Aberrant activation of the Hedgehog pathway drives tumorigenesis of many cancers, including glioblastoma. However, the sensitization mechanism of the G protein-coupled-like receptor smoothened (SMO), a key component of Hedgehog signaling, remains largely unknown. In this study, we describe a novel protein SMO-193a.a. that is essential for Hedgehog signaling activation in glioblastoma. Encoded by circular SMO (circ-SMO), SMO-193a.a. is required for sonic hedgehog (Shh) induced SMO activation, via interacting with SMO, enhancing SMO cholesterol modification, and releasing SMO from the inhibition of patched transmembrane receptors. Deprivation of SMO-193a.a. in brain cancer stem cells attenuates Hedgehog signaling intensity and suppresses self-renewal, proliferation in vitro, and tumorigenicity in vivo. Moreover, circ-SMO/SMO-193a.a. is positively regulated by FUS, a direct transcriptional target of Gli1. Shh/Gli1/FUS/SMO-193a.a. form a positive feedback loop to sustain Hedgehog signaling activation in glioblastoma. Clinically, SMO-193a.a. is more specifically expressed in glioblastoma than SMO and is relevant to Gli1 expression. Higher expression of SMO-193a.a. predicts worse overall survival of glioblastoma patients, indicating its prognostic value. Our study reveals that SMO-193a.a., a novel protein encoded by circular SMO, is critical for Hedgehog signaling, drives glioblastoma tumorigenesis and is a novel target for glioblastoma treatment.
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