Investigating the mechanism of BCL-3-mediated radioresistance in colorectal cancer

Abstract

Colorectal cancer remains the second highest cause of cancer mortality in the UK, despite improvements in detection and treatment. Treatment for locally advanced rectal cancer involves preoperative chemoradiotherapy (nCRT) to reduce rates of recurrence. However, patients that fail to respond to nCRT have a significantly poorer survival rate. Identifying factors promoting radioresistance in tumour cells will aid stratification of treatment to those who will benefit, and identify novel therapeutic targets.
The atypical inhibitor of κB (IκB) protein B Cell Lymphoma 3 (BCL-3) is upregulated in a subset of colorectal cancers, and its expression correlated with poor survival. BCL-3 has recently been implicated in radiotherapy resistance in colorectal cancer, with BCL-3 suppression resulting in increased γH2AX foci formation (a measure of DNA double-strand breaks; DSB) following irradiation, and decreased homologous recombination repair. This study aimed to investigate the mechanism by which BCL-3 promotes radioresistance, hypothesising that the interaction of BCL-3 with histone-modifying enzymes is responsible for its radioprotective effect.
The results show that, independent of a defect in DNA repair, BCL-3 suppression increases DSB formation one minute after irradiation, suggesting that absence of BCL-3 renders cells more susceptible to DSBs. Changes in chromatin structure can influence DSB susceptibility, therefore the effect of BCL-3 on histone acetylation and chromatin structure was assessed, demonstrating regulation of both increases and decreases in histone acetylation and chromatin compaction when suppressed. BCL-3 also regulated histone modification following irradiation, which could impact DSB repair in tumour cells. To investigate the underlying mechanism of these effects, an interactome was generated. Novel BCL-3 interactors which could influence DSB accumulation were identified, and the association with TBLR1, a member of the SMRT complex, further validated. These results highlight the chromatin-regulating potential of BCL-3, and suggest novel mechanisms by which BCL-3 might promote radioresistance. These findings suggest that targeting BCL-3 could radiosensitise rectal cancer cells and improve therapeutic outcomes.

Date of Award	10 Dec 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Ann C Williams (Supervisor) & Adam Christian Chambers (Supervisor)