Latifkar, Arash2021-03-122021-08-272020-08Latifkar_cornellgrad_0058F_11940http://dissertations.umi.com/cornellgrad:11940https://hdl.handle.net/1813/103110202 pagesSpread of tumor cells from their primary sites to vital distant organs and tissues, i.e. metastasis, is the most devastating stage of cancer development. Metastatic tumors grow rapidly, and they rarely respond to therapeutic interventions. Thus, a better understanding of how aggressive cancer cells get into the circulation and colonize the secondary site is essential for blocking metastasis. In Chapter 2, I describe the role of a lysine deacylase in regulating the ability of breast cancer cells to secrete factors that promote their aggressiveness. Specifically, I will discuss the mechanism by which, breast cancer cells can take advantage of SIRT1 downregulation to promote secretion of nanometer sized vesicles, known as exosomes, as well as protein hydrolases capable of degrading the extracellular matrix. The secretion of these factors results in the ability of other cancer cells in microenvironment to become more invasive. I also show that SIRT1 is in fact regulating the activity of an organelle called lysosomes by influencing the expression of a subunit (i.e. ATP6V1A) of the machinery responsible for lysosomal acidification. In Chapter 3, I found that SIRT1 is modulating the RNA stability of the ATP6V1A transcript through deacetylating IGF2BP2, an RNA binding protein that binds to the 3'- untranslated region (UTR) of this transcript. Mechanistically, acetylation of IGF2BP2, under conditions where SIRT1 is downregulated, results in recruitment of the exonuclease XRN2, which promotes the degradation of the ATP6V1A mRNA. I also show that knocking down IGF2BP2 or XRN2 can reverse the effect of SIRT1 downregulation on the cellular secretome. In the final chapter, I will discuss the implication of my findings in cancer and other biological contexts as well as describing outstanding questions that have emerged from my dissertation.encancerexosomesribonucleic Acidsirtuinstumor microenvironmentvesiclesdissertation or thesishttps://doi.org/10.7298/grvj-9v75