DNA methylation: a link between physical activity and reduced prostate cancer progression?

From the Dai, Stanford, and Wright Groups, Public Health Sciences Division

The overall 5-year relative survival rate for prostate cancer is encouragingly high, currently estimated at nearly 98%. Early detection remains a key factor to such favorable outcomes; however, even among men diagnosed at with localized prostate cancer, a small fraction develops metastatic cancer and cancer-specific mortality. Understanding modifiable factors that may reduce the risk for progression to metastatic cancer and the associated mechanisms through which they act are of great interest. Physical activity is believed to be one such factor, a hypothesis supported by recent studies that demonstrate associations between activity and better prostate cancer outcomes. However, an understanding of how physical activity may lead to better outcomes has been limited. A recently published paper in the journal Cancer Epidemiology, Biomarkers & Prevention by Drs. James Dai, Janet Stanford, and Jonathan Wright in the Division of Public Health Sciences provides new preliminary data that yield insight into the molecular basis of this relationship.

Epigenetic modifications regulate gene expression without altering the sequence of DNA itself. DNA methylation, a type of epigenetic modification in which methyl groups are attached to specific DNA locations, can be altered by physical activity. The Fred Hutch researchers hypothesized that changes in DNA methylation in tumor tissue may be a mechanism linking physical activity and lower risk for progression to metastatic-lethal prostate cancer. The new study “is the first to investigate the association between vigorous physical activity and DNA methylation in primary prostate tissues,” said Dr. Dai.

For their analyses, the authors used data collected from 1,354 men diagnosed with clinically localized prostate cancer who self-reported their physical activity levels. Analyses were restricted to levels of vigorous physical activity (defined as leisure time activity that worked up a sweat or lasted for more than 20 minutes) during the year prior to cancer diagnosis. Participants were categorized by frequency of activity: more than three times per week, one to three times per week, or less than one time per week. The authors also analyzed DNA methylation in a subset of participants who underwent radical prostatectomy and had tumor tissue samples available for the molecular analyses.

Graphical representation of survival for time to metastatic-lethal prostate cancer and of differentially methylated region in the promoter region of CRACR2A gene
Survival curve for time to metastatic-lethal prostate cancer in men who exercised vigorously less than once per week versus those who exercised vigorously more than once per week (left panel). Differentially methylated region in the promoter region of CRACR2A gene stratified by frequency of vigorous physical activity (right panel). Image provided by Dr. James Dai

The authors found that progression to metastatic-lethal cancer was significantly lower in men who exercised vigorously at least once a week as compared to those who exercised at that intensity level less than once per week. Because there was no significant difference between the one to three times per week and the more than three times per week exercisers, the authors combined these groups in subsequent analyses. Statistical proportional hazard ratio modeling results were consistent, demonstrating lower risk for progression in the group that exercised vigorously at least once per week (see figure, left panel). Dr. Dai summarized the findings, “In a well-characterized Seattle-based cohort of patients with localized prostate cancer, men who exercised vigorously at least once per week during the year before diagnosis were significantly less likely to develop metastatic–lethal progression when compared with those who exercised vigorously but less frequently.”

DNA methylation levels were then compared between the two groups of patients. The authors conducted an analysis that focused on identifying differentially methylated regions. The majority of the regions did not significantly differ between the two groups. However, the top differentially methylated region, localized to the promoter region of the CRACR2A gene, was significantly different between the two patient groups (see figure, right panel). Nine CpGs within this region were hypomethylated in the group that exercised vigorously at least once per week. When the authors statistically adjusted for vigorous physical activity, hypomethylation at these nine CpGs were associated with reduced risk for progression to metastatic-lethal cancer. This finding suggests that lower methylation in the CRACR2A promoter region may be involved in mediating the effect of vigorous physical activity on risk for cancer progression. CRACR2A encodes a calcium-binding protein that is associated with innate immune responses and interacts with proteins that may regulate intracellular calcium levels.

While this study was the first to assess whether weekly vigorously physical activity and DNA methylation are linked in prostate tumors, the list of follow-up studies is already growing. “The association of exercise and better prostate cancer outcome is strong and consistent with existing evidence. The DNA methylation analysis is exploratory and next step is to design a validation study for the association of CRACR2A hypo-methylation and exercise, as well as formally assessing the mediation of the exercise effect on cancer outcome through DNA methylation,” said Dr. Dai.

In additional ongoing work, collaborative research efforts at Fred Hutch, University of Washington, and Seattle Cancer Care Alliance, including Drs. Stanford and Wright, are investigating the role of exercise and lifestyle in low-grade (the Prostate Cancer Active Lifestyle Study) and metastatic castrate-resistant (the Intense Exercise for Survival Among Men with Metatstatic Castrate-Resistant Prostate Cancer study) prostate cancer. Together, these studies will increase our understanding of the impact of exercise on prostate cancer outcomes.

Fred Hutch/UW Cancer Consortium members James Dai, Janet Stanford, and Jonathan Wright contributed to this research.

This research was supported by the National Cancer Institute.

Dai JY, Wang B, Wang X, Cheng A, Kolb S, Stanford JL, Wright JL. 2019. Vigorous physical activity is associated with lower risk of metastatic-lethal progression in prostate cancer and hypomethylation in the CRACR2A gene. Cancer Epidemiology, Biomarkers & Prevention. doi: 10.1158/1055-9965.EPI-18-0622.