1-s2.0-S1568786422000647-main.pdf (4.49 MB)
BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination
journal contribution
posted on 2023-06-10, 03:16 authored by Christopher Parker, Adam C Chambers, Dustin J Flanagan, Jasmine Wing Yu Ho, Tracey J Collard, Greg Ngo, Duncan M Baird, Penny Timms, Rhys MorganRhys Morgan, Owen J Sansom, Ann C WilliamsThe proto-oncogene BCL-3 is upregulated in a subset of colorectal cancers (CRC), where it has been shown to enhance tumour cell survival. However, although increased expression correlates with poor patient prognosis, the role of BCL-3 in determining therapeutic response remains largely unknown. In this study, we use combined approaches in multiple cell lines and pre-clinical mouse models to investigate the function of BCL-3 in the DNA damage response. We show that suppression of BCL-3 increases ?H2AX foci formation and decreases homologous recombination in CRC cells, resulting in reduced RAD51 foci number and increased sensitivity to PARP inhibition. Importantly, a similar phenotype is seen in Bcl3-/- mice, where Bcl3-/- mouse crypts also exhibit sensitivity to DNA damage with increased ?H2AX foci compared to wild type mice. Additionally, Apc.Kras-mutant x Bcl3-/- mice are more sensitive to cisplatin chemotherapy compared to wild type mice. Taken together, our results identify BCL-3 as a regulator of the cellular response to DNA damage and suggests that elevated BCL-3 expression, as observed in CRC, could increase resistance of tumour cells to DNA damaging agents including radiotherapy. These findings offer a rationale for targeting BCL-3 in CRC as an adjunct to conventional therapies and suggest that BCL-3 expression in tumours could be a useful biomarker in stratification of rectal cancer patients for neo-adjuvant chemoradiotherapy.
History
Publication status
- Published
File Version
- Published version
Journal
DNA RepairISSN
1568-7864Publisher
ElsevierExternal DOI
Volume
115Page range
1-11Article number
a103331Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-04-29First Open Access (FOA) Date
2022-04-29First Compliant Deposit (FCD) Date
2022-04-28Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC