ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer.

Abstract:: We previously described that the KDM5B histone H3 lysine 4 demethylase is an oncogene in estrogen-receptor-positive breast cancer. Here, we report that KDM5A is amplified and overexpressed in basal breast tumors, and KDM5 inhibition (KDM5i) suppresses the growth of KDM5-amplified breast cancer cell lines. Using CRISPR knockout screens in a basal breast cancer cell line with or without KDM5i, we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitizes cells to KDM5i, whereas deletion of RHO-GTPases leads to resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed co-localization of ZBTB7A and KDM5A/B at promoters with high histone H3K4me3 and dependence of KDM5A chromatin binding on ZBTB7A. ZBTB7A knockout altered the transcriptional response to KDM5i at NF-κB targets and mitochondrion-related pathways. High expression of ZBTB7A in triple-negative breast cancer is significantly associated with poor response to neoadjuvant chemotherapy. Our work furthers the understanding of KDM5-mediated gene regulation and identifies mediators of sensitivity to KDM5i.

Authors:: B DiCiaccio, M Seehawer, Z Li, A Patmanidis, T Bui, P Foidart, J Nishida, CS D'Santos, EK Papachristou, M Papanastasiou, AH Reiter, X Qiu, R Li, Y Jiang, X-Y Huang, A Simeonov, SC Kales, G Rai, M Lal-Nag, A Jadhav, M Brown, JS Carroll, HW Long, K Polyak

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