DHHC2, a Palmitoylating Enzyme, is a Key Suppressor of Prostate Cancer Metastasis and Castration Resistance
Abstract
When prostate cancer spreads (metastasizes) to distant organs, it becomes incurable and most patients die within 5 years. Although initially treatable by systemic hormone therapy, distantly spread (metastatic) prostate cancer will invariably develop into an aggressive and lethal form of disease called metastatic castration-resistant prostate cancer (mCRPC), which kills about 28,000 American men yearly. Understanding the major molecular mechanisms of prostate cancer progression will be essential for the prevention and cure of lethal metastatic prostate cancer, at least in a large portion of patients. ZDHHC2, a gene encoding an enzyme (called DHHC2) catalyzing protein palmitoylation (a type of lipid modification), is expressed at significantly lower levels in >50% of metastatic prostate cancer than in primary prostate cancer. This suggests that DHHC2 is potentially a key suppressor of prostate cancer spreading (metastasis) and insensitivity to hormone therapy (castration resistance). However, we know almost nothing about the functions of DHHC2 in prostate cancer spreading and progression. Thus, the goal of the proposed study is to determine (1) whether DHHC2 is really a major brake for prostate cancer spreading and progression to mCRPC and (2) how DHHC2 halts prostate cancer spreading and progression. First, we will use cell culture and mouse models to determine whether increasing the expression of enzymatically active DHHC2, but not enzymatically inactive DHHC2, decelerates prostate cancer spreading and restores the response of prostate cancer to hormone therapy. Second, we will apply a powerful analytical method that we developed to identify almost all proteins that are palmitoylated by DHHC2. Some of these proteins may be key executors of DHHC2 s suppressor functions. In short, the proposed study will lead to, in a few years, the identification of novel prognostic biomarkers that can distinguish aggressive prostate cancer from indolent disease, as well as new therapeutic targets that can be exploited to prevent or diminish prostate cancer spreading and to restore the sensitivity of prostate cancer to hormone therapy, thus dramatically reducing the death toll of prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510167
Entities
People
- Wei Yang
Organizations
- Cedars-Sinai Medical Center
- United States Army