The contribution of miRNA biogenesis and Myc-regulated miRNA in apoptosis and tumorigenesis

Abstract

microRNA (miRNA) are critical mediators of cellular signaling and regulate most biological processes. Thus, it is not surprising that miRNA dysregulation significantly contributes to tumorigenesis. In this dissertation, I have assessed two major forms of miRNA regulation that are frequently compromised in human malignancies, including transcriptional regulation and processing. Using in vitro strategies and genetically engineered mouse models, I assessed the impact of deregulated miRNA processing on the survival of B cells and B cell lymphomas by deleting Dicer, a crucial enzyme in the miRNA biogenesis pathway. Results from these analyses demonstrate that miRNA production is required for normal B cell and B cell lymphoma viability, and, even when the strong tumor suppressive activity of p53 is absent, cells cannot survive. These data provide important knowledge of the cellular requirements of miRNA. Furthermore, my investigations of the transcriptional regulation of the tumor suppressive miR-15 and let-7 families have exposed a novel mechanism of Myc-induced apoptosis. The oncogenic transcription factor Myc regulates the expression of the miR-15 and let-7 families to limit the deleterious consequences of oncogene activation in normal cells. While this mechanism was inactivated in multiple human cancer types, I determined it could be re-activated by targeting histone deacetylase enzymes. Importantly, these data provide insight into the molecular events responsible for the therapeutic effects of HDAC inhibition and contribute new knowledge that should aid in the development of improved cancer therapeutics.