Background. Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy where 5 year survival can fall below 25%. Consequently, there is an urgent need to identify new strategies to improve patient outcomes. Based on the high proportion of TP53 mutations in EOC (96%) and the pivotal role histone modifications can have on tumorigenesis, we proposed to examine links between p53 and the addition of ubiquitin to histone H2B at lysine 120 (H2Bub1).  H2Bub1 has been linked to cancer development and is present at the coding region of p53 gene targets.

Aim: To determine whether p53 modulates histone H2B monoubiquitination in epithelial ovarian cancer.

Method. The chemotherapeutic drug cisplatin was used to activate p53 in the EOC cell line A2780 for up to 24 hours. Target proteins, including H2Bub1, were analysed by western blot. To further explore the relationship between p53 and H2Bub1, wild-type p53 was transfected into the p53 null cell lines H1299 and SKOV3 using pcDNA4-p53 or vector alone for 48 hours.  Furthermore, siRNA was used to down-regulate p53 in the p53 wild-type A2780 cell line. Western blotting was used to analyse target proteins.

Results. H2Bub1 levels were shown to significantly decrease in A2780 cells in response to cisplatin treatment. This response was inversely correlated with an increase in both total p53 and phosphorylated p53. siRNA knockdown of p53 in A2780 cells prevented this decrease in H2Bub1 after cisplatin treatment. Transfection of wild-type p53 into p53-null cells resulted in decreased H2Bub1.

Conclusion. Our results suggest that p53 regulates H2Bub1 levels in EOC. The mechanism of this regulation is yet to be understood; however, given the importance of H2Bub1 in DNA damage repair and transcriptional elongation, and the well established roles of p53, it is likely to be significant in tumorigenesis.