Ágata Carreira

My research focuses on investigating the remodelling of the translation landscape in response to cyclin-dependent kinase 9 (CDK9) inhibition in prostate cancer models. 

Our preliminary data show that CDK9 inhibition activates innate immune response through viral mimicry in PC cells. In MYC over-expressing prostate cancer cells, CDK9 inhibition leads to gross accumulation of mis-spliced RNA. Double-stranded RNA (dsRNA)-activated kinase can recognize these mis-spliced RNAs, and we show that the activity of this kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. Using time-resolved transcriptional profiling (SLAM-seq), targeted proteomics and ChIP-seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes. Strikingly, at the same time, CDK9 inhibition enhances translation as measured by post-translational modifications on the key regulatory proteins and sensitization to inhibitors of protein biosynthesis. CDK9 inhibition stimulates translation of specific proteins, and we show that depletion of CDK9 activity leads to excessive secretion of immunogenic cytokines. However, we do not yet know the extent to which protein biosynthetic machinery is remodelled and if the increased secretion of the cytokines can potentiate the cytotoxic effects of the immune cells.

Additionally, I have a strong research interest in understanding the role of secreted NNMT (eNNMT) in the context of prostate cancer tumour microenvironment (TME), as a follow-up of my previous findings.