Dysregulation and prognostic potential of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) levels in prostate cancer

Abstract

BackgroundPrognostic tools for prostate cancer (PC) are inadequate and new molecular biomarkers may improve risk stratification. The epigenetic mark 5-hydroxymethylcytosine (5hmC) has recently been proposed as a novel candidate prognostic biomarker in several malignancies including PC. 5hmC is an oxidized derivative of 5-methylcytosine (5mC) and can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The present study is the first to investigate the biomarker potential in PC for all four DNA methylation marks in parallel. Thus, we determined 5mC, 5hmC, 5fC, and 5caC levels in non-malignant (NM) and PC tissue samples from a large radical prostatectomy (RP) patient cohort (n = 546) by immunohistochemical (IHC) analysis of serial sections of a tissue microarray. Possible associations between methylation marks, routine clinicopathological parameters, ERG status, and biochemical recurrence (BCR) after RP were investigated.Results5mC and 5hmC levels were significantly reduced in PC compared to NM prostate tissue samples (p ≤ 0.027) due to a global loss of both marks specifically in ERG− PCs. 5fC levels were significantly increased in ERG+ PCs (p = 0.004), whereas 5caC levels were elevated in both ERG− and ERG+ PCs compared with NM prostate tissue samples (p ≤ 0.019). Positive correlations were observed between 5mC, 5fC, and 5caC levels in both NM and PC tissues (p < 0.001), while 5hmC levels were only weakly positively correlated to 5mC in the PC subset (p = 0.030). There were no significant associations between 5mC, 5fC, or ERG status and time to BCR in this RP cohort. In contrast, high 5hmC levels were associated with BCR in ERG− PCs (p = 0.043), while high 5caC levels were associated with favorable prognosis in ERG+ PCs (p = 0.011) and were borderline significantly associated with worse prognosis in ERG− PCs (p = 0.058). Moreover, a combined high-5hmC/high-5caC score was a significant adverse predictor of post-operative BCR beyond routine clinicopathological variables in ERG− PCs (hazard ratio 3.18 (1.54–6.56), p = 0.002, multivariate Cox regression).ConclusionsThis is the first comprehensive study of 5mC, 5hmC, 5fC, and 5caC levels in PC and the first report of a significant prognostic potential for 5caC in PC.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0540-x) contains supplementary material, which is available to authorized users.

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

“…The TET proteins are responsible for the sequential oxidation of 5-mC into 5-hydroxymethylcytosine (5-hmC), then 5-formylcytosine (5-fC), and finally 5-carboxylcytosine (5-caC). 179 5-fC and 5-caC are shortlived intermediates of an active DNA demethylation pathway, while 5-hmC can possibly be regarded as an independent epigenetic marker. The global loss of 5-hmC has recently been proposed as a novel candidate biomarker of the presence of an aggressive tumor with both diagnostic and prognostic implications.…”

“…The global loss of 5-hmC has recently been proposed as a novel candidate biomarker of the presence of an aggressive tumor with both diagnostic and prognostic implications. Reduced 5-hmC levels are observed in many F I G U R E 1 Schematic diagram demonstrating the application of TCM in cancer therapy based on genetics, epigenetics, tumor microenvironment, and cancer stem cells cancers, including prostate, 179 ovarian, 180 melanoma, 181 and lung 182 cancer. In animal disease models, the growth of aggressive tumors can be thwarted by restoring 5-hmC levels via IDH2 or TET2 overexpression.…”

Epigenetic modulations and lineage plasticity in advanced prostate cancer

“…In a similar study, TET proteins were found to suppress tumor progression and invasion partly through downregulation of critical gene methylation. 29 Storebjerg et al 30 reported TET family proteins and the epigenetic marker 5hmC to be novel candidate prognostic biomarkers. Further studies are warranted to explore the epigenetic mechanisms of TET proteins in CRPC and NEPC.…”

Global DNA 5hmC and CK19 with 5hmC positives cell contents represent a promising biomarker for predicting prognosis in small hepatocellular carcinoma

“…The study displayed that high 5hmC content is an independent prognosis factor of unfavorable PFS and OS in pediatric SHCC. Low 5hmC contents in most solid tumors usually means higher tumor grade and worse results [3,11,13,14,27,28]. Nevertheless, our findings displayed that high 5hmC contents were independently relevant to inferior OS in SHCC and 5hmC was possibly correlated with tumor occurrence and malignant transformation.…”

“…5-position DNA methylation of cytosine (5mC) is an epigenetic cancer marker. Several studies have shown that the ten eleven translocation (TET) protein family initiates an active DNA demethylation pathway, leading to the transformation of 5mC into 5-hydroxymethylcytosine (5hmc) [11]. 5hmc, a novel epigenetic biomarker, is change the view of tumor epigenetics.…”