Journal
HUMAN MOLECULAR GENETICS
Volume 25, Issue 24, Pages 5460-5471Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw362
Keywords
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Funding
- Cancer Council NSW, Australia [RG13-10]
- Australian Research Council [FT100100489]
- National Health and Medical Research Council [APP1004799]
- Australia Postgraduate Award and Sydney Medical School - Northern scholarship, Australia
- U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council Victoria
- Queensland Cancer Fund
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Foundation of Western Australia
- Cancer Council Tasmania
- National Health and Medical Research Council of Australia (NHMRC) [ID400413, 10400281]
- NHMRC [ID310670, ID628903]
- Cancer Institute NSW [12/RIG/1-17, 15/RIG/1-16]
- University of Sydney Cancer Research Fund
- Cancer Institute NSW through the Sydney-West Translational Cancer Research Centre
- Australian Research Council [FT100100489] Funding Source: Australian Research Council
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Enzymatic factors driving cancer-associated chromatin remodelling are of increasing interest as the role of the cancer epigenome in gene expression and DNA repair processes becomes elucidated. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) is a central histone modification that functions in histone cross-talk, transcriptional elongation, DNA repair, maintaining centromeric chromatin and replication-dependent histone mRNA 3'-end processing, as well as being required for the differentiation of stem cells. The loss of global H2Bub1 is seen in a number of aggressive malignancies and has been linked to tumour progression and/or a poorer prognosis in some cancers. Here, we analyse a large cohort of high-grade serous ovarian cancers (HGSOC) and show loss of global H2Bub1 in 77% (313 of 407) of tumours. Loss of H2Bub1 was seen at all stages (I-IV) of HGSOC, indicating it is a relatively early epigenomic event in this aggressive malignancy. Manipulation of key H2Bub1 E3 ubiquitin ligases, RNF20, RNF40 and BRCA1, in ovarian cancer cell line models modulated H2Bub1 levels, indicative of the role of these RING finger ligases in monoubiquitination of H2Bub1 in vitro. However, in primary HGSOC, loss of RNF20 protein expression was identified in just 6% of tumours (26 of 424) and did not correlate with global H2Bub1 loss. Similarly, germline mutation of BRCA1 did not show a correlation with the global H2Bub1 loss. We conclude that the regulation of tumour-associated H2Bub1 levels is complex. Aberrant expression of alternative histone-associated 'writer' or 'eraser' enzymes are likely responsible for the global loss of H2Bub1 seen in HGSOC.
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