EPIGENETICS INFORMING FUTURE TREATMENT STRATEGIES FOR HIGH GRADE SEROUS OVARIAN CANCER – LOOKING TO HISTONES, UBIQUITIN AND CHROMATIN RELAXATION — ASN Events
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  2. Afternoon Tea/Poster Session
  3. EPIGENETICS INFORMING FUTURE TREATMENT STRATEGIES FOR HIGH GRADE SEROUS OVARIAN CANCER – LOOKING TO HISTONES, UBIQUITIN AND CHROMATIN RELAXATION

EPIGENETICS INFORMING FUTURE TREATMENT STRATEGIES FOR HIGH GRADE SEROUS OVARIAN CANCER – LOOKING TO HISTONES, UBIQUITIN AND CHROMATIN RELAXATION (#112)

Kristie A Dickson 1 , Alex J Cole 1 , Catherine Kennedy 2 , Adele Clarkson 3 , Gregory B Gard 4 , Angela Chou 5 , Anthony J Gill 3 , Rory Clifton-Bligh 1 , Anna deFazio 2 , Deborah J Marsh 1
  1. Hormones and Cancer, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
  2. Gynaecological Oncology and Westmead Institute for Cancer Research, University of Sydney, Sydney, NSW, Australia
  3. Anatomical Pathology, Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia
  4. Obstetrics and Gynaecology, Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia
  5. Anatomical Pathology, SYDPATH St Vincent's Hospital, Sydney, NSW, Australia
Histones are the most abundant proteins bound to DNA in eukaryotic cells. Post-translational modifications of histones, such as methylation, acetylation and ubiquitination, influence accessibility to DNA of factors involved in DNA damage repair and transcription. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) leads to physical separation of chromatin strands and active recruitment of factors involved in histone cross-talk, transcription and repair of DNA damage. Monoubiquitination is controlled by E3 ubiquitin ligases and deubiquitinases (DUBs). Both BRCA1 and the ring finger protein RNF20 are H2Bub1-associated E3 ubiquitin ligases. Given the known involvement of BRCA1 in high grade serous cancer (HGSC), this study aimed to determine the influence of BRCA1 mutation and RNF20 levels on H2Bub1 in this malignancy. We investigated a large HGSC patient cohort using immunohistochemistry to determine global tumour levels of H2Bub1 and RNF20, and analysed the association of H2Bub1 levels with germ-line BRCA1 mutation status. Additionally, we used HGSC cell line models to determine the relationship between BRCA1 expression, RNF20 and H2Bub1. GlobalH2Bub1was lost in over 70% of HGSC. No significant correlation was observed between germ-line BRCA1 mutation status or RNF20 levels and H2Bub1; however, manipulation of BRCA1 and RNF20 expression in HGSC cell line models influenced global H2Bub1 levels. H2Bub1 regulation is complex, appearing to rely on multiple enzymatic processes. Targeting H2Bub1 may pose an attractive strategy for the development of epigenetic based therapies for HGSC.