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

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.

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

“…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 cancers, including prostate, ovarian, melanoma, and lung cancer. In animal disease models, the growth of aggressive tumors can be thwarted by restoring 5‐hmC levels via IDH2 or TET2 overexpression .…”

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

“…There are three different isoforms of DNMT enzymes that show different and non-redundant roles: DNTM1 is critical to maintaining the proper DNA methylation during mitosis, whereas DNMT3A and DNMT3B are more implicated in the methylation process during embryogenesis [16]. Globally, the readout of the DNMTs activity is the hypermethylation of DNA, which is usually associated with the silencing of gene expression [17][18][19]. Aberrant DNMT levels has been detected in many different cancer types through genome-wide analyses, which highlighted a~5-10% increased methylation on CpG islands in cancer specimens compared to normal counterparts, with a consequent silencing of several tumor-suppressor genes (i.e., CDKN2B, RASSF1A, GATA4, CDH1), further supporting the tight correlation between epigenetics abnormalities and cancer initiation and progression [20][21][22][23][24].…”

“…On the opposite side, there are TET1 and TET2, the ten-eleven translocation enzymes, methyl-cytosine dioxygenases known as the DNA methylation "Erasers", responsible for catalytically converting 5mC to hydroxy-methyl-cytosine (5hmC) [19,25].…”

Integrative prognostic subtype discovery in high‐grade serous ovarian cancer

“…High‐grade serous ovarian cancer (HGSC) accounts for approximately 70% of women diagnosed with epithelial ovarian cancer . Despite initial aggressive treatment, tumor debulking and platinum/taxane‐based chemotherapy, patients always have an extremely poor clinical outcome with 5‐year survival rate less than 40% . Although several determinants have known to be significant to the prognostic of ovarian cancer, there is no fully validated prognostic‐related mechanism currently clear.…”

“…1 Despite initial aggressive treatment, tumor debulking and platinum/taxane-based chemotherapy, patients always have an extremely poor clinical outcome with 5-year survival rate less than 40%. 2,3 Although several determinants have known to be significant to the prognostic of ovarian cancer, there is no fully validated prognostic-related mechanism currently clear. Further understanding of the underlying biological characteristics and molecular pathogenesis of ovarian cancer are required to improve clinical outcome.…”