Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

Clin Cancer Res. 2018 Mar 15;24(6):1389-1401. doi: 10.1158/1078-0432.CCR-17-1958. Epub 2017 Dec 20.


Purpose: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation.Experimental Design: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically.Results: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease.Conclusions: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. Clin Cancer Res; 24(6); 1389-401. ©2017 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5-Methylcytosine / analogs & derivatives*
  • 5-Methylcytosine / metabolism
  • Animals
  • Cell Survival / drug effects
  • Cellular Reprogramming / genetics*
  • Combined Modality Therapy
  • Cystadenocarcinoma, Serous / etiology*
  • Cystadenocarcinoma, Serous / metabolism*
  • Cystadenocarcinoma, Serous / mortality
  • Cystadenocarcinoma, Serous / pathology
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dioxygenases / genetics
  • Dioxygenases / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Neoplasm Grading
  • Ovarian Neoplasms / etiology*
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Recurrence
  • Survival Analysis
  • Xenograft Model Antitumor Assays


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • TET3 protein, human
  • Dioxygenases
  • TET2 protein, human