Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer

Abstract

Background5-Hydroxymethylcytosine (5hmC) is converted from 5-methylcytosine (5mC) by a group of enzymes termed ten-eleven translocation (TET) family dioxygenases. The loss of 5hmC has been identified as a hallmark of most types of cancer and is related to tumorigenesis and progression. However, the role of 5hmC in bladder cancer is seldom investigated. Vitamin C was recently reported to induce the generation of 5hmC by acting as a cofactor for TET dioxygenases. In this study, we explored the role of 5hmC in bladder cancer and the therapeutic efficacy of vitamin C in increasing the 5hmC pattern.Results5hmC was decreased in bladder cancer samples and was related to patient overall survival. Genome-wide mapping of 5hmC in tumor tissues and vitamin C-treated bladder cancer cells revealed that 5hmC loss was enriched in cancer-related genes and that vitamin C treatment increased 5hmC levels correspondingly. Vitamin C treatment shifted the transcriptome and inhibited the malignant phenotypes associated with bladder cancer cells in both in vitro cell lines and in vivo xenografts.ConclusionsThis study provided mechanistic insights regarding the 5hmC loss in bladder cancer and a rationale for exploring the therapeutic use of vitamin C as a potential epigenetic treatment for bladder cancer.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0527-7) contains supplementary material, which is available to authorized users.

Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

“…In some cases, there have been no benefits. However, new knowledge regarding the pharmacokinetic properties of Vit-C, and recent preclinical studies, have revived interest in the utilization of high-dose Vit-C for cancer treatment [132][133][134][135][136][137][138][139][140][141][142][143][144][145]. Similar is the case of using IV Vit-C as antiviral, especially for the recent Covid19 [146][147][148][149][150].…”

Dietary antioxidants remodel DNA methylation patterns in chronic disease

“…This increase in 5‐hmC levels was confirmed to be mediated by TET proteins in embryonic cells as well as cancer cells (Minor, Court, Young, & Wang, ). Accordingly, vitamin C has been investigated in disease models, specifically cancer, as a TET‐activating compound increasing 5‐hmC levels (Peng et al, ). For instance, in bladder cancer, where genome‐wide mapping of 5‐hmC revealed loss of 5‐hmC in cancer‐related genes, vitamin C treatment led to increased 5‐hmC levels at gene‐specific loci, a shift in the transcriptome profile and inhibition of the malignant phenotypes (Peng et al, ).…”

“…Accordingly, vitamin C has been investigated in disease models, specifically cancer, as a TET‐activating compound increasing 5‐hmC levels (Peng et al, ). For instance, in bladder cancer, where genome‐wide mapping of 5‐hmC revealed loss of 5‐hmC in cancer‐related genes, vitamin C treatment led to increased 5‐hmC levels at gene‐specific loci, a shift in the transcriptome profile and inhibition of the malignant phenotypes (Peng et al, ). A positive correlation between plasma concentration of vitamin C and hydroxymethylation of leukocyte DNA was further observed in patients with inflammatory bowel disease, adenomatous polyps and colorectal cancer (Starczak et al, ).…”

“…TET activity, in turn, converts a methylated cytosine to 5‐hmC and further oxidized forms (Figure ), which eventually leads to DNA demethylation and gene activation, including genes from the Nrf2 antioxidant pathway (Yin et al, ; Peng et al, ; Figure ). In the study by Peng et al (), the Nrf2‐mediated oxidative stress response pathway was the most abundant pathway associated with enhancers that overlapped with vitamin C‐increased 5‐hmC peaks in bladder cancer (Peng et al, ). This finding provides evidence that DNA demethylation induction in response to vitamin C plays a vital role in the antioxidant effects of vitamin C (Peng et al, ).…”

“…In the study by Peng et al (), the Nrf2‐mediated oxidative stress response pathway was the most abundant pathway associated with enhancers that overlapped with vitamin C‐increased 5‐hmC peaks in bladder cancer (Peng et al, ). This finding provides evidence that DNA demethylation induction in response to vitamin C plays a vital role in the antioxidant effects of vitamin C (Peng et al, ).…”