文章：

阻断三甲基鸟苷合酶1（TGS1）可抑制犬肉瘤的锚定非依赖性生长

Blocking tri-methylguanosine synthase 1 (TGS1) stops anchorage-independent growth of canine sarcomas 

原文发布日期：2023-06-29 

英文摘要：

Tri methylguanosine synthase 1 (TGS1) is the enzyme that hyper methylates the hallmark 7-methyl-guanosine cap (m7G-cap) appended to the transcription start site of RNAs. The m7G-cap and the eIF4E-cap binding protein guide canonical cap-dependent translation of mRNAs, whereas hyper methylated cap, m2,2,7G-cap (TMG) lacks adequate eIF4E affinity and licenses entry into a different translation initiation pathway. The potential role for TGS1 and TMG-capped mRNA in neoplastic growth is unknown. Canine sarcoma has high translational value to the human disease. Cumulative downregulation of protein synthesis in osteosarcoma OSCA-40 was achieved cooperatively by siTGS1 and Torin-1. Torin-1 inhibited the proliferation of three canine sarcoma explants in a reversible manner that was eliminated by siRNA-downregulation of TGS1. TGS1 failure prevented the anchorage-independent growth of osteo- and hemangio-sarcomas and curtailed sarcoma recovery from mTOR inhibition. RNA immunoprecipitation studies identified TMG-capped mRNAs encoding TGS1, DHX9 and JUND. TMG-tgs1 transcripts were downregulated by leptomycin B and TGS1 failure was compensated by eIF4E mRNP-dependent tgs1 mRNA translation affected by mTOR. The evidence documents TMG-capped mRNAs are hallmarks of the investigated neoplasms and synergy between TGS1 specialized translation and canonical translation is involved in sarcoma recovery from mTOR inhibition. Therapeutic targeting of TGS1 activity in cancer is ripe for future exploration. 

摘要翻译： 

三甲基鸟苷合成酶1（TGS1）是一种对RNA转录起始位点特征性7-甲基鸟苷帽（m7G-cap）进行超甲基化的酶。m7G-cap与eIF4E帽结合蛋白共同指导经典的帽依赖性mRNA翻译，而超甲基化的m2,2,7G-cap（TMG）因缺乏足够的eIF4E亲和力，转而进入不同的翻译起始通路。TGS1和TMG帽化mRNA在肿瘤生长中的潜在作用尚不明确。犬类肉瘤对人类疾病具有高度转化研究价值。通过联合使用siTGS1和Torin-1，我们在骨肉瘤OSCA-40细胞中实现了蛋白质合成的累积性下调。Torin-1以可逆方式抑制三种犬肉瘤外植体的增殖，这种抑制效应可通过siRNA下调TGS1消除。TGS1功能缺失阻止了骨肉瘤和血管肉瘤的锚定非依赖性生长，并削弱了肉瘤从mTOR抑制中的恢复能力。RNA免疫沉淀研究鉴定出编码TGS1、DHX9和JUND的TMG帽化mRNA。TMG-tgs1转录本受到瘦霉素B的下调，而TGS1功能缺失可通过mTOR调控的eIF4E mRNP依赖性tgs1 mRNA翻译得以补偿。该证据表明TMG帽化mRNA是本研究所涉肿瘤的特征性标志，且TGS1特异性翻译与经典翻译之间的协同作用参与肉瘤从mTOR抑制中的恢复过程。针对癌症中TGS1活性的治疗靶向研究已具备未来探索价值。

原文链接：

Blocking tri-methylguanosine synthase 1 (TGS1) stops anchorage-independent growth of canine sarcomas