Abstract
Despite major advances in targeted melanoma therapies, drug resistance limits their efficacy. Long noncoding RNAs (lncRNAs) are transcriptome elements that do not encode proteins but are important regulatory molecules. LncRNAs have been implicated in cancer development and response to different therapeutics and are thus potential treatment targets; however, the majority of their functions and molecular interactions remain unexplored. In this study, we identify a novel cytoplasmic intergenic lincRNA (MIRAT), which is upregulated following prolonged MAPK inhibition in NRAS mutant melanoma and modulates MAPK signaling by binding to the MEK scaffold protein IQGAP1. Collectively, our results present MIRAT’s direct modulatory effect on the MAPK pathway and highlight the relevance of cytoplasmic lncRNAs as potential targets in drug resistant cancer.
Highlights
Long noncoding RNAs were identified as important parts of cell’s transcriptome and are thought to be regulatory elements of cancer initiation and progression
We performed de novo transcriptome analyses (RNA-Seq) to identify Long noncoding RNAs (lncRNAs) differentially expressed in melanoma cells with acquired resistance to small molecule inhibitors of the MAPK cascade
Acquired drug resistance to MAPK inhibitors in melanoma leads to the expression of the lincRNA MIRAT (MAPK Inhibitor Resistance Associated Transcript)
Summary
Long noncoding RNAs (lncRNAs) were identified as important parts of cell’s transcriptome and are thought to be regulatory elements of cancer initiation and progression. They are defined as RNA molecules longer 200 base pairs which are transcribed but not translated to proteins[18,19]. We performed de novo transcriptome analyses (RNA-Seq) to identify lncRNAs differentially expressed in melanoma cells with acquired resistance to small molecule inhibitors of the MAPK cascade. Our results offer first evidence of a cytoplasmic lncRNA contributing to targeted inhibitor resistance in melanoma with the potential to open up new therapeutic avenues to further improve treatment
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