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Direct but No Transgenerational Effects of Decitabine and Vorinostat on Male Fertility

ABSTRACT: Epigenetic drugs actively altering the epigenome of tumours have been developed for use in anti-cancer therapies. However, these drugs could potentially also affect the DNA methylome of spermatozoa that seems to be essential for male fertility. Here, we analysed possible direct and transgenerational effects of the epigenetic drug decitabine on the DNA methylome of spermatozoa. Our analysis revealed the absence of gross differences between the spermatozoal methylome of decitabine treated and untreated animals as well as between their F3 generations. Interestingly, the methylomes of spermatozoa from the selected mice of the F3-generations were also highly similar to the analysed parental samples.

ORGANISM(S): Mus musculus

PROVIDER: GSE59575 | GEO | 2015/03/03

SECONDARY ACCESSION(S): PRJNA255653

REPOSITORIES: GEO

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Project description:Background: In high-grade serous ovarian cancer (HGSOC) intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations, but frequent epigenetic alterations including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated. Aims of this study were to explore how representative HGSOC PDXs are for their corresponding patient tumors methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. Methods: Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450K. Further, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the predictive/prognostic value of the identified genes. Results: Only 0.6-1.0% of all analyzed CpGs (388,696 CpGs) changed significantly (p<0.01) during propagation showing that HGSOC PDXs are epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6% of CpG sites in comparison to untreated PDXs (p<0.01, FDR<10%). Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g. Src family kinase pathway). Particularly, C-terminal Src kinase (CSK) gene was successfully validated for epigenetic regulation in different PDX models and ovarian cancer cell lines. Low CSK methylation and high CSK expression were both significantly associated (p<0.05) with improved progression free survival and overall survival in HGSOC patients. Conclusion: HGSOC PDXs resemble the global epigenome of patients over many generations, which can be modulated by epigenetic drugs. Novel epigenetically regulated genes such as CSK and related pathways were identified in HGSOC. Our results encourage future application of PDXs for cancer epigenome studies.

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Direct but No Transgenerational Effects of Decitabine and Vorinostat on Male Fertility

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