Epigenetic DNA modifications and vitamin C in prostate cancer and benign prostatic hyperplasia: Exploring similarities, disparities, and pathogenic implications

Abstract

Objectives: Benign Prostatic Hyperplasia (BPH) and Prostate Cancer (PC) are very common pathologies among aging men. Both disorders involve aberrant cell division and differentiation within the prostate gland. However, the direct link between these two disorders still remains controversial. A plethora of works have demonstrated that inflammation is a major causative factor in both pathologies. Another key factor involved in PC development is DNA methylation and hydroxymethylation.

Methods: A broad spectrum of parameters, including epigenetic DNA modifications and 8-oxo-7,8-dihydro-2'-deoxyguanosine, was analyzed by two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry in tissues of BPH, PC, and marginal one, as well as in leukocytes of the patients and the control group. In the same material, the expression of TETs and TDG genes was measured using RT-qPCR. Additionally, vitamin C was quantified in the blood plasma and within cells (leukocytes and prostate tissues).

Results: Unique patterns of DNA modifications and intracellular vitamin C (iVC) in BPH and PC tissues, as well as in leukocytes, were found in comparison with control samples. The majority of the alterations were more pronounced in leukocytes than in the prostate tissues.

Conclusions: Characteristic DNA methylation/hydroxymethylation and iVC profiles have been observed in both PC and BPH, suggesting potential shared molecular pathways between the two conditions. As a fraction of leukocytes may be recruited to the pathological tissues and can migrate back into the circulation/blood, the observed alterations in leukocytes may reflect dynamic changes associated with the PC development, suggesting their potential utility as early markers of prostate cancer development.

Keywords: Benign prostatic hyperplasia; Epigenetic DNA modifications; Prostate cancer; TET enzymes; Vitamin C.

Fig. 1

Levels of DNA modifications: (A) 5-mdC, (B) 5-hmdC, (C) 5-fdC, (D) 5-cadC, (E) 5-hmdU, and (F) 8-oxodG in leukocytes’ DNA from healthy controls; patients with benign prostatic hyperplasia (BPH) and prostate cancer (PC). The results were presented as medians, interquartile ranges, and 95 % confidence intervals.

Fig. 2

Comparison of vitamin C: (A) in blood plasma of healthy controls, patients with BPH and PC, (B) inside the leukocytes of healthy controls, patients with BPH and PC, (C) in normal/marginal prostate tissues; cancer prostate tissues; and benign prostatic hyperplasia (BPH) tissues. The results were presented as medians, interquartile ranges, and 95 % confidence intervals.

Fig. 3

Levels of DNA modifications (A) 5-mdC, (B) 5-hmdC, (C) 5-fdC, (D) 5-cadC, (E) 5-hmdU, and (F) 8-oxodG in normal/marginal prostate tissues; cancer prostate tissues; and benign prostatic hyperplasia (BPH) tissues. The results were presented as medians, interquartile ranges, and 95 % confidence intervals.

Fig. 4

Correlations between the levels of DNA epigenetic modifications (A) 5-fdC, (B) 5-cadC, (C) 5-hmdU, and intracellular vitamin C concentration in cancer prostate tissues.

Fig. 5

Expressions of (A) TET1, (B) TET2, (C) TET3, and (D) TDG mRNA in leukocytes from healthy controls; patients with benign prostatic hyperplasia (BPH) and prostate cancer (PC). The results were presented as medians, interquartile ranges, and 95 % confidence intervals.

Fig. 6

Expressions of (A) TET1, (B) TET2, (C) TET3, and (D) TDG mRNA in normal/marginal prostate tissues, cancer prostate tissues, and BPH tissues. The results were presented as medians, interquartile ranges, and 95 % confidence intervals.