The E3 ubiquitin ligase RNF20 writes a central histone modification, influencing the chromatin landscape and demonstrating potential for targeting as a cancer therapeutic
- Hormones and Cancer Group, Kolling Institute, University of Sydney, Sydney, NSW, Australia.
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
E3 ubiquitin ligases are responsible for the final stage of the enzymatic ubiquitination cascade, where they transfer ubiquitin from an E2 conjugating enzyme to a lysine on the recognised substrate. The most common family of E3 ligases are RING (Really Interesting New Gene) domain proteins. Using immunohistochemistry, we have shown that the ring finger protein RNF20 is strongly expressed in 87% (379 of 424) of high-grade serous ovarian cancer (HGSOC) (1). RNF20 functioning in a heterodimer with RNF40 is the main E3 ligase complex responsible for monoubiquitination of histone H2B at lysine 120 (H2Bub1). This active histone mark leads to an open chromatin configuration favouring DNA access by transcriptional complexes and DNA repair proteins. We have down-regulated RNF20 in ovarian cancer cell lines to investigate the potential of targeting this E3 ligase to overcome resistance to platinum therapies that is a major problem for the clinical management of women with ovarian cancer. Cells were studied as monolayers and spheroid cultures. We have shown that down-regulation of RNF20 decreases levels of H2Bub1, consistent with a closed chromatin configuration. Clonogenic cell survival assays following the treatment of ovarian cancer cell lines with cisplatin showed an impaired ability of cells in which RNF20 had been down-regulated to form colonies. This work provides preliminary evidence that developing strategies to therapeutically down-regulate RNF20 may increase the efficacy of standard-of-care chemotherapy for women with ovarian cancer. (1) Dickson KA et al., Hum Mol Genet (2016).