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ZBTB7A and KDM5 activity co-regulate NF-kB target gene expression and oxidative phosphorylation in triple negative breast cancer

ABSTRACT: We previously described that the KDM5B histone H3 lysine 4 (H3K4) demethylase is an oncogene in estrogen receptor-positive breast cancer. Here we report that KDM5A is amplified and overexpressed in basal breast tumors and is associated with chemotherapy resistance. Using CRISPR knockout viability screens -/+ KDM5 inhibition (KDM5i), we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitized to KDM5i, whereas knockout of RHO-GTPases led to resistance. ChIP-seq and RNA-seq analyses revealed colocalization of ZBTB7A and KDM5A/B at promoters with high H3K4me3 and dependence of KDM5A binding on ZBTB7A. ZBTB7A knockout altered transcriptional response to KDM5i specifically at NF-kB target genes, oxidative phosphorylation, and E2F-driven proliferation pathways. Our work furthers understanding of KDM5-mediated gene regulation in breast cancer and identified key pathways mediating sensitivity to KDM5i.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Kornelia Polyak

PROVIDER: MSV000094452 | MassIVE | Tue Apr 02 08:16:00 BST 2024

REPOSITORIES: MassIVE

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