Investigating the importance of CBX2’s structural motifs for its chromatin interactions and pro-oncogenic epigenetic regulatory function in triple negative breast cancer

Dobrowinski, Wojciech

Abstract

Epigenetics is the study of the change in gene expression patterns that are not caused by direct alterations in the DNA nucleotide sequence but instead are as a result of the dynamic remodelling of the chromatin state. Regulation of the chromatin landscape is mediated via coordination between methylation of DNA and chemical modifications of the associated histone proteins. The activity and expression of the epigenetic regulatory proteins modulating the histone modifications has been shown to be dysregulated in a range of cancers, moreover, due to the reversible nature of the histone modifications these epigenetic regulatory proteins have emerged as potential therapeutic targets. CBX2 is an epigenetic regulatory protein shown to be overexpressed in triple negative breast cancer (TNBC) and to play a role in regulating TNBC cell growth. It functions as the chromatin interacting subunit of polycomb repressive complex 1 (PRC1) which condenses the chromatin and thus represses the transcription of genes. This study aimed to investigate which structural motifs of CBX2 are integral for its ability to interact with the chromatin in TNBC. Genotypic and phenotypic changes in TNBC cell line models were assessed following the overexpression of CBX2 and structural motif deficient CBX2 variants. The effect of rescue of CBX2 expression following siRNA mediated CBX2 knockdown with the CBX2 variants was also assessed. We identified the chromodomain of the CBX2 as the structural motif important for CBX2s ability to regulate TNBC cell growth, the catalytic activity of the PRC1 complex and regulation of its target genes. This suggests that therapeutically targeting the chromodomain of CBX2 may be a viable strategy for treating the aberrant epigenome created by CBX2 overexpression in hard-to-treat cancers such as TNBC.

Citation

Dobrowinski, W. (2022). Investigating the importance of CBX2’s structural motifs for its chromatin interactions and pro-oncogenic epigenetic regulatory function in triple negative breast cancer. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4291232

• Thesis Type: Thesis
• Deposit Date: May 16, 2023
• Publicly Available Date: May 16, 2023
• Keywords: Biomedical science
• Public URL: https://hull-repository.worktribe.com/output/4291232
• Award Date: Dec 1, 2022