Approximately 90% of prostate cancer deaths arise from the metastatic spread of primary tumors;however, there is a profound lack of therapies that can efficiently prevent prostate cancer metastasis. Therefore, identifying genes and underlying mechanisms that convert localized prostate cancer to an aggressive tumor holds the key for reducing the mortality of the disease. Sirt1, a mammalian Histone Deacetylase, has been shown involved in aging, metabolism, cell proliferation, growth and survival. While many studies have focused on the role of Sirt1 in controlling cell survival and growth, little is known about Sirt1 regulation of cell adhesion and motility. Objective/Hypothesis: Our studies have demonstrated that: A) Sirt1 knockdown results in tighter cell-cell adhesion, and reduced cell motility and invasiveness of prostate cancer cells in vitro. B) Sirt1 colocalizes and associates with E-cadherin, and Sirt1 knockdown upregulates E-cadherin level and increases its adhesion junction localization. C) Sirt1 is over-expressed in human prostate carcinoma tissues, and its expression correlates with prostate cancer Gleason Score. Therefore, our central hypothesis is that over-expression of Sirt1 regulates prostate cancer cell adhesion and migration by suppressing E-cadherin abundance and adhesion junction localization, Sirt1 may thereby play a role in prostate cancer cell progression.
Specific Aim : 1). Elucidate the mechanism of Sirt1 regulating E-cadherin dependent prostate cancer cell adhesion. We will study the mechanism by which Sirt1 regulates E- cadherin protein abundance, and determine the regulation of Sirt1 on E-cadherin localization through its deacetylase activity. 2). Elucidate the effect of Sirt1 knockdown and/or inhibition on prostate cancer metastasis in vivo. We will determine whether Sirt1 knockdown or Sirt1 inhibitor reduce prostate cancer metastasis in an orthotopic xenograft mode. Cancer Relevance: The establishment of the Sirt1 function as a metastasis inducer and understanding of how it regulates tumor cell adhesion and migration, should lead to new target of treatment modality and molecular targeting for prostate cancer therapy.
In this proposed study, we will elucidate the role of Sirt1 in prostate cancer metastasis and study the mechanism of Sirt1 in the regulation of prostate cancer cell adhesion. The establishment of the Sirt1 function as a metastasis inducer and understanding of how it regulates tumor cell migration, should lead to new target of treatment modality and molecular targeting for prostate cancer therapy.
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