The Palmitoylating Enzyme DHHC11 Promotes Prostate Cancer Progression and Metastasis
Abstract
Once prostate cancer cells spread to distant organs and form metastases visible on an X-ray, the disease can no longer be cured, and most patients die within 2 to 3 years. Thus, it is critical to understand at the molecular level how prostate cancer cells spread and thrive in distant organs in order to prevent and treat lethal metastatic prostate cancer. Global analyses of mRNAs in prostate cancer tissue specimens showed that ~90% of metastatic prostate tumors (and ~30% of primary prostate tumors) express the ZDHHC11 gene at significantly higher levels than normal prostate tissues. Furthermore, patients with high levels of ZDHHC11 expression in their tumors are about five times more likely to have a metastatic recurrence than those with low levels of ZDHHC11 expression. ZDHHC11 encodes an enzyme called DHHC11, which attaches long-chain fatty acids (especially palmitic acid) to specific cysteines on proteins. This enzyme process is called protein palmitoylation, which dynamically changes the location and activity of many proteins. Studies have shown that abnormal protein palmitoylation contributes to many human diseases, including prostate cancer. Taken together, DHHC11 is potentially a novel key factor in prostate cancer metastasis and a promising drug target. But does enzyme-active DHHC11 increase prostate cancer spread and severity? If so, what mechanism does DHHC11 employ to increase the spread and severity of prostate cancer? These conceptually novel and clinically relevant questions will be addressed in the proposed research plan, utilizing our unique combination of various technical skills. First, we will use cell culture and mouse models to determine whether taking away DHHC11 from prostate cancer cells decreases the spread and growth of prostate cancer. We will also determine whether adding enzyme-active DHHC11, not enzyme-inactive DHHC11, to DHHC11-depleted cells allows prostate cancer to spread and grow again. Second, we will use powerful analytical methods to identify almost all of the proteins that bind to, are controlled by, or are palmitoylated by DHHC11. Some of these proteins are necessary for DHHC11 to increase prostate cancer spread and severity. Notably, the roles and mechanisms of palmitoylating enzymes have never been studied in prostate cancer spread before, so the proposed research will add a new dimension to our understanding of prostate cancer metastasis. Targeting DHHC11 should not cause any major side effects because it is rarely found in normal organs other than the testis. We envision that our research will lead to Phase 1/2 clinical trials to test specific, potent, and orally available inhibitors of DHHC11 enzyme activity if enzyme-active DHHC11 is needed for prostate cancer to spread and grow or inhibitors of DHHC11 interaction with specific binding partners if enzyme-inactive DHHC11 is needed. DHHC11 and its interacting or substrate proteins in tumor-derived extracellular vesicles can be turned into a non-invasive liquid biopsy biomarker to find the right patients who are most likely to benefit from anti-DHHC11 drugs. If successful, patients with non-metastatic castration-resistant prostate cancer (M0 CRPC) will live much longer without getting metastases and associated symptoms such as bone pain and breaks. Patients with only a few prostate cancer metastases (called oligometastases) will also benefit from these drugs, which inhibit cancer cells from spreading to more organs. If DHHC11 protects metastatic prostate cancer cells from dying, targeting DHHC11 can trigger cell death and thus shrink existing prostate cancer metastases. These early phase trials could lead to Phase 3 clinical trials, which would make it possible for DHHC11 inhibitors to be used regularly in the clinic. Thus, the proposed project is directly relevant to two FY22 PCRP Overarching Challenges: (1) define the biology of prostate cancer progression to lethal prostate cancer to reduce death and (2) impr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310028
Entities
People
- Wei Yang
Organizations
- Cedars-Sinai Medical Center
- United States Army