Poly (ADP-ribose) polymerase 1 transcriptional regulation: A novel crosstalk between histone modification H3K9ac and ETS1 motif hypomethylation in BRCA1-mutated ovarian cancer
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Da Li1, Fang-Fang Bi1, Ji-Min Cao2, Chen Cao3, Chun-Yan Li4, Bo Liu5, Qing Yang1
1 Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
2 Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
3 Department of Pathology, Chinese PLA General Hospital, Beijing, China
4 Department of Histology and Embryology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
5 Department of Laboratory Medicine, No. 1 Hospital of China Medical University, Shenyang, China
Da Li and Qing Yang, email:
Keywords: PARP1, H3K9ac, ETS1, BRCA1, Ovarian cancer
Received: October 29, 2013 Accepted: December 29, 2013 Published: December 29, 2013
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.
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