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

Clin Epigenetics. 2018 Jul 13;10(1):94. doi: 10.1186/s13148-018-0527-7.


Background: 5-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.

Results: 5hmC 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.

Conclusions: This 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.

Keywords: 5-Hydroxymethylcytosine; Bladder cancer; TET; Vitamin C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives*
  • 5-Methylcytosine / metabolism
  • Aged
  • Animals
  • Ascorbic Acid / administration & dosage*
  • Ascorbic Acid / pharmacology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Regulatory Networks / drug effects*
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Prognosis
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA
  • Survival Analysis
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism
  • Xenograft Model Antitumor Assays


  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Ascorbic Acid