An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks.
An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks.
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DOI：
10.1186/s12943-021-01401-y
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发表时间：
2021-09-08
期刊：
影响因子：
37.3
通讯作者：
Santisteban P
中科院分区：
文献类型：
--
作者：
Ramírez-Moya J;Miliotis C;Baker AR;Gregory RI;Slack FJ;Santisteban P
作用于RNA的腺苷脱氨酶（ADAR）通过催化腺苷转化为肌苷（A-to-I）来修饰许多细胞RNA，并且它们的失调与几种癌症相关。我们最近发现，甲状腺肿瘤中A-to-I编辑水平升高，ADAR 1在甲状腺癌细胞进展中具有重要功能。然而，由ADAR 1调节或编辑的下游效应物以及ADAR 1失调在甲状腺癌中的意义仍然不清楚。我们进行了全转录组测序，以确定ADAR 1失调对全局基因表达，RNA剪接和编辑的影响。通过分析细胞活力、增殖、侵袭和亚核定位以及通过蛋白质和基因表达分析来研究基因沉默或RNA编辑的影响。我们报告了CDK 13在甲状腺癌中的致癌功能，并确定了一个新的ADAR 1依赖的RNA编辑事件，发生在其转录本的编码区。CDK 13在肿瘤样品中被显著过度编辑（c.308A > G），并且功能分析显示这种编辑事件促进癌细胞标志。最后，我们发现CDK 13编辑增加了蛋白质的核仁丰度，并且这一事件可能至少部分解释了ADAR 1失调产生的剪接的全球变化。总的来说，我们的数据支持A-to-I编辑作为癌症进展的重要途径，并强调了可能用于治疗甲状腺和其他癌症的新机制。在线版本包含补充材料，可通过10.1186/s12943-021-01401-y获得。
Adenosine deaminases acting on RNA (ADARs) modify many cellular RNAs by catalyzing the conversion of adenosine to inosine (A-to-I), and their deregulation is associated with several cancers. We recently showed that A-to-I editing is elevated in thyroid tumors and that ADAR1 is functionally important for thyroid cancer cell progression. The downstream effectors regulated or edited by ADAR1 and the significance of ADAR1 deregulation in thyroid cancer remain, however, poorly defined. We performed whole transcriptome sequencing to determine the consequences of ADAR1 deregulation for global gene expression, RNA splicing and editing. The effects of gene silencing or RNA editing were investigated by analyzing cell viability, proliferation, invasion and subnuclear localization, and by protein and gene expression analysis. We report an oncogenic function for CDK13 in thyroid cancer and identify a new ADAR1-dependent RNA editing event that occurs in the coding region of its transcript. CDK13 was significantly over-edited (c.308A > G) in tumor samples and functional analysis revealed that this editing event promoted cancer cell hallmarks. Finally, we show that CDK13 editing increases the nucleolar abundance of the protein, and that this event might explain, at least partly, the global change in splicing produced by ADAR1 deregulation. Overall, our data support A-to-I editing as an important pathway in cancer progression and highlight novel mechanisms that might be used therapeutically in thyroid and other cancers. The online version contains supplementary material available at 10.1186/s12943-021-01401-y.
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影响因子：
2.7
作者：
Didion JP;Martin M;Collins FS
通讯作者：
Collins FS
影响因子：
7
作者：
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影响因子：
1.2
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Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
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Ruden, Douglas M.
影响因子：
2
作者：
Crow, Yanick J.;Chase, Diana S.;Schmidt, Johanna Lowenstein;Szynkiewicz, Marcin;Forte, Gabriella M. A.;Gornall, Hannah L.;Oojageer, Anthony;Anderson, Beverley;Pizzino, Amy;Helman, Guy;Abdel-Hamid, Mohamed S.;Abdel-Salam, Ghada M.;Ackroyd, Sam;Aeby, Alec;Agosta, Guillermo;Albin, Catherine;Allon-Shalev, Stavit;Arellano, Montse;Ariaudo, Giada;Aswani, Vijay;Babul-Hirji, Riyana;Baildam, Eileen M.;Bahi-Buisson, Nadia;Bailey, Kathryn M.;Barnerias, Christine;Barth, Magalie;Battini, Roberta;Beresford, Michael W.;Bernard, Genevieve;Bianchi, Marika;de Villemeur, Thierry Billette;Blair, Edward M.;Bloom, Miriam;Burlina, Alberto B.;Carpanelli, Maria Luisa;Carvalho, Daniel R.;Castro-Gago, Manuel;Cavallini, Anna;Cereda, Cristina;Chandler, Kate E.;Chitayat, David A.;Collins, Abigail E.;Sierra Corcoles, Concepcion;Cordeiro, Nuno J. V.;Crichiutti, Giovanni;Dabydeen, Lyvia;Dale, Russell C.;D'Arrigo, Stefano;De Goede, Christian G. E. L.;De Laet, Corinne;De Waele, Liesbeth M. H.;Denzler, Ines;Desguerre, Isabelle;Devriendt, Koenraad;Di Rocco, Maja;Fahey, Michael C.;Fazzi, Elisa;Ferrie, Colin D.;Figueiredo, Antonio;Gener, Blanca;Goizet, Cyril;Gowrinathan, Nirmala R.;Gowrishankar, Kalpana;Hanrahan, Donncha;Isidor, Bertrand;Kara, Lent;Khan, Nasaim;King, Mary D.;Kirk, Edwin P.;Kumar, Ram;Lagae, Lieven;Landrieu, Pierre;Lauffer, Heinz;Laugel, Vincent;La Piana, Roberta;Lim, Ming J.;Lin, Jean-Pierre S. -M.;Linnankivi, Tarja;Mackay, Mark T.;Marom, Daphna R.;Lourenco, Charles Marques;McKee, Shane A.;Moroni, Isabella;Morton, Jenny E. V.;Moutard, Marie-Laure;Murray, Kevin;Nabbout, Rima;Nampoothiri, Sheela;Nunez-Enamorado, Noemi;Oades, Patrick J.;Olivieri, Ivana;Ostergaard, John R.;Perez-Duenas, Belen;Prendiville, Julie S.;Ramesh, Venkateswaran;Rasmussen, Magnhild;Regal, Luc;Ricci, Federica;Rio, Marlene;Rodriguez, Diana;Roubertie, Agathe;Salvatici, Elisabetta;Segers, Karin A.;Sinha, Gyanranjan P.;Soler, Doriette;Spiegel, Ronen;Stoedberg, Tommy I.;Straussberg, Rachel;Swoboda, Kathryn J.;Suri, Mohnish;Tacke, Uta;Tan, Tiong Y.;Naude, Johann te Water;Teik, Keng Wee;Thomas, Maya Mary;Till, Marianne;Tonduti, Davide;Valente, Enza Maria;Van Coster, Rudy Noel;van der Knaap, Marjo S.;Vassallo, Grace;Vijzelaar, Raymon;Vogt, Julie;Wallace, Geoffrey B.;Wassmer, Evangeline;Webb, Hannah J.;Whitehouse, William P.;Whitney, Robyn N.;Zaki, Maha S.;Zuberi, Sameer M.;Livingston, John H.;Rozenberg, Flore;Lebon, Pierre;Vanderver, Adeline;Orcesi, Simona;Rice, Gillian I.
通讯作者：
Rice, Gillian I.
影响因子：
12.3
作者：
Blow MJ;Grocock RJ;van Dongen S;Enright AJ;Dicks E;Futreal PA;Wooster R;Stratton MR
通讯作者：
Stratton MR