Valentina Tassinari1,2, Valeriana Cesarini1,3, Sara Tomaselli1, Zaira Ianniello4, Domenico Alessandro Silvestris1, Lavinia Ceci Ginistrelli4, Maurizio Martini5,6, Biagio De Angelis1, Gabriele De Luca7, Lucia Ricci Vitiani7, Alessandro Fatica4, Franco Locatelli1,8, Angela Gallo9. 1. Oncohaematology Department, IRCCS Ospedale Pediatrico Bambino Gesu, Viale di San Paolo 15, 00146, Rome, Italy. 2. Present address: Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy. 3. Present address: Department of Biomedical Sciences, Institute of Translational Pharmacology, National Research Council of Italy (CNR), Rome, Italy. 4. Department of Biology and Biotechnology "Charles Darwin", La Sapienza University of Rome, Rome, Italy. 5. Department of Women's, Children's and Public Health Studies, Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy. 6. Department of Health Science and Public Health, Institute of Pathology, Largo F. vito 1, 00168, Rome, Italy. 7. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy. 8. Department of Pediatrics, La Sapienza University of Rome, Rome, Italy. 9. Oncohaematology Department, IRCCS Ospedale Pediatrico Bambino Gesu, Viale di San Paolo 15, 00146, Rome, Italy. angela.gallo@opbg.net.
Abstract
BACKGROUND: N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) RNA editing are two of the most abundant RNA modification events affecting adenosines in mammals. Both these RNA modifications determine mRNA fate and play a pivotal role in tumor development and progression. RESULTS: Here, we show that METTL3, upregulated in glioblastoma, methylates ADAR1 mRNA and increases its protein level leading to a pro-tumorigenic mechanism connecting METTL3, YTHDF1, and ADAR1. We show that ADAR1 plays a cancer-promoting role independently of its deaminase activity by binding CDK2 mRNA, underlining the importance of ADARs as essential RNA-binding proteins for cell homeostasis as well as cancer progression. Additionally, we show that ADAR1 knockdown is sufficient to strongly inhibit glioblastoma growth in vivo. CONCLUSIONS: Hence, our findings underscore METTL3/ADAR1 axis as a novel crucial pathway in cancer progression that connects m6A and A-to-I editing post-transcriptional events.
BACKGROUND: N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) RNA editing are two of the most abundant RNA modification events affecting adenosines in mammals. Both these RNA modifications determine mRNA fate and play a pivotal role in tumor development and progression. RESULTS: Here, we show that METTL3, upregulated in glioblastoma, methylates ADAR1 mRNA and increases its protein level leading to a pro-tumorigenic mechanism connecting METTL3, YTHDF1, and ADAR1. We show that ADAR1 plays a cancer-promoting role independently of its deaminase activity by binding CDK2 mRNA, underlining the importance of ADARs as essential RNA-binding proteins for cell homeostasis as well as cancer progression. Additionally, we show that ADAR1 knockdown is sufficient to strongly inhibit glioblastoma growth in vivo. CONCLUSIONS: Hence, our findings underscore METTL3/ADAR1 axis as a novel crucial pathway in cancer progression that connects m6A and A-to-I editing post-transcriptional events.
Authors: Leng Han; Lixia Diao; Shuangxing Yu; Xiaoyan Xu; Jie Li; Rui Zhang; Yang Yang; Henrica M J Werner; A Karina Eterovic; Yuan Yuan; Jun Li; Nikitha Nair; Rosalba Minelli; Yiu Huen Tsang; Lydia W T Cheung; Kang Jin Jeong; Jason Roszik; Zhenlin Ju; Scott E Woodman; Yiling Lu; Kenneth L Scott; Jin Billy Li; Gordon B Mills; Han Liang Journal: Cancer Cell Date: 2015-10-01 Impact factor: 31.743
Authors: Francesca Rapino; Sylvain Delaunay; Florian Rambow; Zhaoli Zhou; Lars Tharun; Pascal De Tullio; Olga Sin; Kateryna Shostak; Sebastian Schmitz; Jolanda Piepers; Bart Ghesquière; Latifa Karim; Benoit Charloteaux; Diane Jamart; Alexandra Florin; Charles Lambert; Andrée Rorive; Guy Jerusalem; Eleonora Leucci; Michael Dewaele; Marc Vooijs; Sebastian A Leidel; Michel Georges; Marianne Voz; Bernard Peers; Reinhard Büttner; Jean-Christophe Marine; Alain Chariot; Pierre Close Journal: Nature Date: 2018-06-20 Impact factor: 49.962
Authors: Nian Liu; Katherine I Zhou; Marc Parisien; Qing Dai; Luda Diatchenko; Tao Pan Journal: Nucleic Acids Res Date: 2017-06-02 Impact factor: 16.971