Artículo del mes
enero 2022

An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks

Referencia artículo:
Mol Cancer. 2021 Sep 8;20(1):115. doi: 10.1186/s12943-021-01401-y. PMID: 34496885; PMCID: PMC8424981
En este trabajo hemos establecido un nuevo mecanismo de acción de la enzima responsable de la edición del RNA, denominada ADAR1, tiene un papel oncogénico en cáncer de tiroides. Hemos descrito que esta enzima es responsable de editar a la proteína CDK13, confiriendo unas características tumorales más agresivas en las células tiroideas. Esta edición, que se produce en su región codificante, cambia la localización subcelular de CDK13 y puede explicar el cambio de splicing alternativo observado tras el silenciamiento de ADAR1 en estas células. Nuestros datos demuestran que la edición del RNA es una vía relevante en la progresión del cáncer de tiroides y muestran un nuevo mecanismo que puede ser utilizado para nuevas terapias en cáncer de tiroides y otros cánceres.
Resumen
Background: 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. Methods: 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 Results: 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. Conclusions: 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.
Sobre el grupo investigador