Epigenetic Aging in TMPRSS2 Fusion-Negative African American Prostate Cancer
Abstract
Scientific Objective and Rationale: Great strides are being made in the dissection of the causes of prostate cancer, in part by undertaking large-scale studies in which all the genes in a prostate cancer are studied and their alterations are mapped. This is immensely powerful and has revealed novel insight into the causes of prostate cancer (PCa) and potential treatment options. However, some of the molecular markers described in European American (EA) prostate cancer patients are not commonly found in African American (AA) prostate cancer patients. One such marker in EA men arises frequently from the fusion of two genes to give a chimeric fusion gene known as TMPRSS2 fusion genes, which in turn drives PCa. Given that PCa tends to arise at a younger age in AA men and is not commonly found with the TMPRSS2 fusion gene, we have aimed to identify cancer drivers in AA men who are TMPRSS2 fusion negative. Specifically, we have undertaken a series of studies of EA and AA prostate cell models to identify disease drivers that are unique or significantly accentuated in AA PCa. These studies have been focused around the hormone vitamin D. This hormone is made in response to sunlight exposure and known to control how cells grow as well as to control bone strength. This is important, as researchers have shown clearly that AA PCa patients have lower levels of vitamin D, and the way it signals may be altered for example in relation to the immune system and could be important to make immunotherapy more effective. Our studies have now revealed for the first time that the vitamin D receptor strongly regulates genes in AA prostate cells related to the circadian rhythm and the control of what is known as the “epigenetic clock.” This is a measurement of the way cells can age, which can be more quickly than calendar age and predict a range of diseases. We have identified a molecular mechanism centered on vitamin D receptor signaling that is disrupted, leading to acceleration of this clock, known as epigenetic aging. We have also extended this mechanism to vitamin D receptor signaling that regulates small non-coding microRNA molecules, which arise in the patient’s tumor and are detectable in the serum. These microRNA have very strong potential to be exploited as biomarkers of disease and, in this case, to potentially predict epigenetic aging. This has led us to the innovative proposal that vitamin D receptor signaling in AA PCa is at the crossroads of biological and psychosocial causes of PCa health disparities, namely that VDR signaling is mechanistically linked with regulation of the epigenetic clock and its disruption is a cancer driver. Application of Our Research: Which Patients? Despite all the research in prostate cancer, it remains challenging to identify which patients need treatment and at which stage. The current research is aimed at investigating prostate cancer, and in the absence of the TMPRSS2 fusion gene, defining how Vitamin D signaling can be used to slow down epigenetic aging and improve the impact of androgen deprivation therapy. Therefore, our goal is to identify aggressive TMPRSS2 fusion negative prostate cancer in AA men and establish how this therapy could be leveraged in men receiving androgen deprivation therapy. Clinical Benefit? AA men living in the United States are at risk of being vitamin D deficient, and our research is particularly focused on designing a serum test for microRNA expression that can be cheaply undertaken to measure the prostate effectiveness of vitamin D signaling and its impact on the epigenetic clock. In this way, we propose to be able to monitor prostate health and detect the emergence of prostate cancer such that a man can be appropriately treated. Timeline to Achieve a Patient-Related Outcome? We work at two university centers, both of which are very active in undertaking cancer health disparities research and translating this to patient support and outcome
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010373
Entities
People
- Moray J Campbell
Organizations
- Ohio State University
- United States Army