Impact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer
Tennakoon, Jayantha 1969-
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What mechanisms govern a cellular phenotype is a fascinating question for which answers are yet being sought. The work presented in this dissertation is an effort to address two fundamental questions, which relate to cellular transition of pluripotent stem cells to a differentiated state and the ability of prostate cancer to have increased proliferative potential. Dicer is an evolutionary conserved RNAse III type endoribonuclease enzyme, which plays a pivotal role in the biogenesis of microRNAs and silencing RNAs (siRNAs). Within the first chapter herein using in vitro cultures of embryonic stem cells, I show that loss of Dicer leads to changes in the ES cell epigenome resulting in a shift in transcriptionally favorable versus transcriptionally unfavorable histone modifications and thereby affect gene expression critical for precise cellular differentiation. In the second chapter, employing a combination of molecular biological and modern metabolomics approaches I show that androgen signaling deregulated in almost all forms of metastatic prostate cancers can lead to increased mitochondrial biogenesis and ATP production affording a distinct proliferative advantage. The underlying mechanism is linked to androgen mediated AMPK- PGC-1α signaling which results increased oxidative capacity in addition to elevated glycolytic capacity quite well established in numerous types of cancers. The pathway uncovered provides an interesting option for targeted therapeutics of prostatic cancers that are particularly resistant to androgen ablation therapies. Finally in the third chapter I show the significance of Dicer in maintaining expression levels of developmentally critical mammalian imprinted genes. The combined results of this thesis provide mechanistic insights into developmentally critical cellular pathways in embryonic stem cells and cancer having high potential to be manipulated in stem cell and molecular intervention based therapeutics.