I study chemical modifications in RNA molecules, including methyltransferases like METTL3 and the role that m6A plays in the regulation of miRNA processing, particularly in the context of cancer formation and metastasis.
Using bioinformatics, molecular and cellular approaches to analyze groups of genes that were altered in highly metastatic compared to poorly metastatic parental populations of breast cancer cells, we identified three miRNAs to be downregulated in breast and bone metastasis (Tavazoie et al., 2008). Furthermore, we identified the transcription factor SOX4 as a miR335 target gene that promotes breast cancer metastasis. We have recently systematically and unbiasedly identified TMEM2 as a downstream target and mediator of SOX4’s effects on breast cancer metastatic cell invasion. Both SOX4 and TMEM2 associates with clinical cancer progression (Lee et al., 2016). Additionally, trying to understand global mechanisms of miRNA processing that could be disrupted in cancer, we discovered that the RNA modification m6A facilitates primary miRNA recognition and miRNA biogenesis and identified HNRNPA2B1 as a nuclear bridge between m6A modified RNA and the miRNA processing machinery. These experiments allowed the discovery of the microRNA biogenesis as an unexpected molecular process regulated by m6A. We are now focused on understanding the impact of m6A RNA modification in cancer initiation and progression.