BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination

• Published in: DNA repair Vol. 115; p. 103331
• Main Authors: Parker, Christopher, Chambers, Adam C., Flanagan, Dustin J., Ho, Jasmine Wing Yu, Collard, Tracey J., Ngo, Greg, Baird, Duncan M., Timms, Penny, Morgan, Rhys G., Sansom, Owen J., Williams, Ann C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2022; Elsevier
• Subjects: Animals; Cell Line, Tumor; Cisplatin - therapeutic use; Colorectal cancer/DNA Damage response/Therapy response/Chemoradiotherapy/Homologous recombination; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; DNA Damage; Homologous Recombination; Humans; Mice; H2AX; LCCRT; CRISPR; IR; HR; PARP; siRNA; Colorectal cancer/DNA Damage response/Therapy response/Chemoradiotherapy/Homologous recombination; BCL-3; DSB; DDR; CRC; NHEJ
• ISSN: 1568-7864; 1568-7856; 1568-7856
• DOI: 10.1016/j.dnarep.2022.103331

The 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 γH2AX 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 γH2AX 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.