Biology subjects

Ramirez-Moya, J.

Publications and source records attributed to Ramirez-Moya, J..

2 recordsLinked to original sources

bioRxiv2024

ADAT2/3-mediated tRNA editing promotes cancer cell growth and tumorigenicity

Transfer RNAs (tRNAs) are subject to various chemical modifications that influence their stability or function. Adenosine to Inosine (A-to-I) editing in the tRNA anticodon at position A34 is an important modification that expands anticodon-codon recognition at the wobble position and is required for normal mRNA translation. The relevance of tRNA editing in cancer remains unexplored. Here we show that the genes encoding the ADAT2/3 deaminase complex, responsible for A-to-I tRNA editing in humans, are commonly amplified and/or overexpressed in several tumor types including liposarcoma (LPS). We find that knockdown of the ADAT complex suppresses LPS cell growth and tumorigenicity. Mechanistically, we find that decreased tRNA editing upon ADAT2 depletion leads to defective translation of a subset of mRNAs. Thus, ADAT-mediated tRNA modification promotes oncogenesis by enhancing the translation of growth promoting mRNAs that are enriched in NNC codons that lack cognate tRNAs and therefore depend on A-I tRNA editing for decoding and mRNA translation. Our results uncover an oncogenic role of tRNA editing and identify ADAT2/3 as a potential new cancer therapeutic target.

cancer biology↗

bioRxiv2018

Impaired miRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness

The global downregulation of miRNAs (miRs) is emerging as a common hallmark of cancer. However, the mechanisms underlying this phenomenon are not well known. We identified that the oncogenic miR-146b-5p attenuates miRNA biosynthesis by targeting DICER1 and reducing its expression. DICER1 overexpression inhibited all the miR-146b-induced aggressive phenotypes in thyroid cells. Systemic injection of an antimiR-146b in mice with orthotopic thyroid tumors suppressed tumor growth and recovered DICER1 levels. Notably, DICER1 downregulation promoted proliferation, migration, invasion and epithelial-mesenchymal transition through miR downregulation. Our analysis of TCGA revealed a general decrease in DICER1 expression in thyroid cancer that was associated with a worse clinical outcome. Administration of the small molecule enoxacin to promote DICER1 complex activity reduced tumor aggressiveness both in vitro and in vivo. Overall, our data establish DICER1 as a tumor suppressor and that the oncogenic miR-146b contributes to its downregulation. Moreover, this study highlights a potential therapeutic application of RNA-based therapies including miR-inhibitors and restoration of the biogenesis machinery, which may provide treatments in for thyroid and other cancers.

cancer biology↗