Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) plays a critical role in ovarian cancer progression. However, the epigenetic mechanism regulating PARP1 transcription remains largely unknown. Here, we show that the hypomethylated ETS1 motif is a key regulatory element for the PARP1 gene in BRCA1-mutated ovarian cancer. Mechanistically, the ETS1 motif hypomethylation-mediated increase of active histone marker H3K9ac and transcription factor ETS1 enrichment synergistically activates PARP1 transcription. Clinicopathological data indicate that a hypomethylated ETS1 motif was associated with high-grade tumors (P = 0.026) and pN1 (P = 0.002). Univariate survival analysis demonstrated an association between the hypomethylated ETS1 motif and an increased risk of death in BRCA1-mutated ovarian cancer patients. Our findings imply that the genetic (such as BRCA1 mutation) and epigenetic mechanisms (such as hypomethylated ETS1 motif, and histone modification H3K9ac and transcription factor ETS1 binding) are jointly involved in the malignant progression of PARP1-related ovarian cancer.
Highlights
Ovarian cancer is characterized by a high mortality rate among gynecologic malignancy worldwide [1]
Our previous results suggested that hypomethylation of the promoter region, especially around the ETS1 motif may be responsible for Poly (ADP-ribose) polymerase 1 (PARP1) overexpression in BRCA1-mutated serous ovarian cancer [7]
Our previous results suggested that promoter hypomethylation, especially around the ETS1 and ETS2 motifs, may be involved in the up-regulation of PARP1 expression in BRCA1-mutated ovarian cancer
Summary
Ovarian cancer is characterized by a high mortality rate among gynecologic malignancy worldwide [1]. In 2005, two pivotal studies showed that BRCA-deficient cells were especially sensitive to chemical inhibitors of poly (ADP-ribose) polymerase (PARP), which plays a critical role in single-stranded DNA break repair, presumably due to the lack of homologous recombination-dependent DNA repair [5,6]. These findings have raised significant concerns about PARP in BRCA-deficient ovarian cancer. The present study was undertaken to investigate PARP1 transcriptional regulation from genetic (BRCA1 mutation) and epigenetic (promoter methylation, histone modifications and transcription factor binding) aspects, and to provide novel insight into epigenetic changemediated abnormal PARP1 expression in BRCA1-mutated ovarian cancer progression
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