Modulators of sensitivity to KDM5 inhibition in basal breast cancer

Abstract

We previously identified KDM5B, encoding a histone H3 lysine 4 (H3K4) demethylase, as an oncogene in luminal breast cancer associated with endocrine resistance. Here we describe that KDM5A is frequently amplified and overexpressed in basal breast tumors and is associated with chemotherapy resistance. To better understand the biological relevance of KDM5 activity in basal breast cancer, we performed whole-genome CRISPR knockout viability screens in a KDM5A- amplified basal breast cancer line -/+ KDM5 inhibition (KDM5i). We found that loss of the transcription factor ZBTB7A and core SAGA complex increased sensitivity to KDM5i, whereas knockout of RHO-GTPases led to resistance. Integrated ChIP-seq and RNA-seq analyses revealed that ZBTB7A and KDM5s co-localize at promoters with high H3K4me3 signal and that half of KDM5A binding is dependent on ZBTB7A. This loss in KDM5A binding upon ZBTB7A knockout is associated with decreased gene expression, indicating a role in gene activation at these sites. Interestingly, ZBTB7A is associated with both gene activation and repression depending on whether it binds to promoter or non-promoter regions, respectively. ZBTB7A knockout has a pleiotropic effect on the transcriptional response to KDM5i, in which it modulates the KDM5i- induced innate immune signaling and NF-kB target gene expression programs. Additionally, ZBTB7A knockout and KDM5i coordinate to alter cell state, in which KDM5i leads to a loss in basal-like gene expression and ZBTB7A knockout induces mesenchymal-like gene expression. Together, this work furthers our understanding of KDM5-mediated gene regulation in basal breast cancer and identifies key pathways that mediate sensitivity to KDM5 inhibition, such as the ZBTB7A transcription factor, SAGA complex, and RHO-GTPases.