1. Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.
- Author
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Tucker DW, Getchell CR, McCarthy ET, Ohman AW, Sasamoto N, Xu S, Ko JY, Gupta M, Shafrir A, Medina JE, Lee JJ, MacDonald LA, Malik A, Hasselblatt KT, Li W, Zhang H, Kaplan SJ, Murphy GF, Hirsch MS, Liu JF, Matulonis UA, Terry KL, Lian CG, and Dinulescu DM
- Subjects
- 5-Methylcytosine metabolism, Animals, Cell Survival drug effects, Combined Modality Therapy, 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, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasm Grading, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Prognosis, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Recurrence, Survival Analysis, Xenograft Model Antitumor Assays, 5-Methylcytosine analogs & derivatives, Cellular Reprogramming genetics, Cystadenocarcinoma, Serous etiology, Cystadenocarcinoma, Serous metabolism, Epigenesis, Genetic, Ovarian Neoplasms etiology, Ovarian Neoplasms metabolism
- Abstract
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 ., (©2017 American Association for Cancer Research.)
- Published
- 2018
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