Loss of ZDHHC-Mediated Scribble Palmitoylation Disrupts Cell Polarity and Promotes Prostate Cancer Progression
Abstract
Scientific Objects and Rationale: Prostate cancer is the most frequently diagnosed and one of the leading causes of cancer deaths in the US. For early-stage prostate cancers, hormone-blocking therapy has shown good clinical efficacy. However, prostate cancer does eventually progress and invade to distal organs, a process known as metastasis. Metastatic prostate cancer carries a very poor prognosis and is resistant to therapeutics. Little is known of how prostate cancer progresses and metastasizes, and it is critical and urgent to understand this hallmark of prostate cancer progression. To develop effective targeted and personalized new therapeutics, it is important to understand the signaling pathways regulating prostate cancer progression. In normal prostate tissue, the cells are well-organized in a highly ordered fashion, a phenomena known as cell polarity. In metastatic prostate cancer, these structures are disrupted. We now understand that several proteins, including a protein called Scribble, are involved in such regulation, blocking prostate cancer cells from progressing and metastasizing. Scribble requires a lipid modification (adding the 16-carbon fatty acid palmitate to its tail) for its function, misregulation of this modification can compromise Scribble?s activity and promote prostate cancer progression. This process is mediated by enzymes known as protein palmitoyl acyltransferases (PATs). We have identified ZDHHC7 is the PAT regulate Scribble, and we aim to understand how ZDHHC7 and Scribble are involved in prostate cancer progression and metastasis. We will further explore the molecular mechanisms of prostate cancer progression. Such knowledge can guide us to discover new therapeutic targets for cancer drug discovery. The objective of this project is to explore the novel idea of how cell polarity is misregulated in prostate cancer and how its misregulation is linked to prostate cancer progression and metastasis. Moreover, we will test whether therapeutic intervention of cell polarity could block PC progression. Ultimate Applicability of the Research: As there is no effective treatment for advanced prostate cancer, the discovery of new mechanisms and therapeutic targets would be very important to the treatment of metastatic prostate cancers. Our research aims to understand the misregulation of cell polarity in metastatic prostate cancer and will likely reveal new therapeutic targets for cancer drug discovery. Likely Contributions to Advancing the Field of Prostate Cancer Research: The innovative studies we plan to carry out are believed to be transformative. By providing new mechanisms to understand how prostate cancer progress and metastasis, we are addressing the urgent needs to identify therapeutic targets to combat prostate cancer progression, an often neglected research area. In addition, we linked fatty acid metabolism and protein lipidation to the regulation of prostate cancer progression, provided mechanistic insights into how obesity and metabolic disorders are linked to cancer progression. This in turn will revolutionize the study of prostate cancer progression and metastasis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710361
Entities
People
- Xu Wu
Organizations
- Massachusetts General Hospital
- United States Army