Transcriptional Regulators in Cancer: Exploring YAP/TAZ-Driven Signaling Mechanisms and Super Enhancer Elements
Many cellular hallmarks of cancer are driven by dysregulation of their transcriptional programs. This work centers on exploring both regulatory elements of transcription and consequences of aberrant transcriptional activity in cancer cells. The first chapter investigates how the molecular mechanisms driven by hyperactivation of the transcriptional coactivators, YAP and TAZ, promote growth and survival of NF2-mutant tumors. We demonstrate that silencing of YAP/TAZ is sufficient to induce tumor regression in pre-establish NF2-mutant orthotopic kidney tumors. Through further investigation, we discover that YAP/TAZ depletion alters the cellular metabolic state controlling cell growth and survival. Furthermore, we identify a lysosome-mediated cAMP- PKA/EPAC-dependent activation of RAF-MEK-ERK signaling as a novel resistance mechanism to YAP/TAZ inhibition. We establish the clinical significance of these findings by correlating the transcriptomes of metabolic and lysosomal genes with a YAP/TAZ transcriptional signature.The second chapter builds on the existing concept of super enhancers (SEs), which are traditionally defined as long stretches of active enhancers with exceptionally high occupancy of transcription factors (TFs) and co-activators. Using an unbiased approach, we conducted a large- scale analysis of available ChIP-seq data to identify true high occupancy SEs in five widely- studied cell lines. We found these actual high occupancy SEs to minimally overlap with classic SEs. Through additional analyses comparing chromatin binding profiles and intrinsic DNA sequence characteristics, we conclude our newly-defined SEs are distinct from classic SEs and regular enhancers due to being broadly accessible, GC-rich regions whose high occupancy of anchoring TFs, trans TFs, and cofactors regulate highly-expressed genes.
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