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

• Published in: Cell reports (Cambridge) 2024-12, Vol.43 (12), p.114991, Article 114991
• Main Authors: DiCiaccio, Benedetto, Seehawer, Marco, Li, Zheqi, Patmanidis, Andriana, Bui, Triet, Foidart, Pierre, Nishida, Jun, D’Santos, Clive S., Papachristou, Evangelia K., Papanastasiou, Malvina, Reiter, Andrew H., Qiu, Xintao, Li, Rong, Jiang, Yijia, Huang, Xiao-Yun, Simeonov, Anton, Kales, Stephen C., Rai, Ganesha, Lal-Nag, Madhu, Jadhav, Ajit, Brown, Myles, Carroll, Jason S., Long, Henry W., Polyak, Kornelia
• Format: Article
• Language: English
• Subjects: breast cancer; CP: Cancer; CRISPR screen; histone demethylase; mitochondrial signaling
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114991

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. [Display omitted] •Deletion of ZBTB7A transcription factor and core SAGA complex synergizes with KDM5 inhibitors•KDM5A chromatin binding is altered by ZBTB7A deletion•Loss of ZBTB7A potentiates KDM5 inhibition-induced signaling changes by modulating NF-κB•High ZBTB7A in triple-negative breast cancer with no response to neoadjuvant chemotherapy DiCiaccio et al. conducted a CRISPR viability screen to characterize mechanisms of response and resistance to KDM5 inhibition in basal breast cancer and identified the ZBTB7A transcription factor as a key mediator of KDM5A chromatin binding. Deletion of ZBTB7A alters NF-κB and mitochondrial signaling following KDM5 inhibition.