Impact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer

dc.contributor.advisorGunaratne, Preethi H.
dc.contributor.advisorFrigo, Daniel E.
dc.contributor.committeeMemberWells, Dan E.
dc.contributor.committeeMemberGao, Xiaolian
dc.contributor.committeeMemberZwaka, Thomas P.
dc.creatorTennakoon, Jayantha 1969-
dc.date.accessioned2015-08-24T02:04:49Z
dc.date.available2015-08-24T02:04:49Z
dc.date.createdAugust 2013
dc.date.issued2013-08
dc.date.updated2015-08-24T02:04:49Z
dc.description.abstractWhat 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.
dc.description.departmentBiology and Biochemistry, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/10657/1027
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectDicer
dc.subjectMouse embryonic stem cells
dc.subjectEpigenome
dc.subjectAndrogen signaling
dc.subjectAMPK
dc.subjectPGC1a
dc.subjectProstate cancer
dc.subject.lcshBiology
dc.titleImpact of Dicer on the Embryonic Stem Cell Epigenome and Androgen Mediated AMPK-PGC-1α Signaling in Prostate Cancer
dc.type.dcmiText
dc.type.genreThesis
thesis.degree.collegeCollege of Natural Sciences and Mathematics
thesis.degree.departmentBiology and Biochemistry, Department of
thesis.degree.disciplineBiology
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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