ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer
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
- Malvina Papanastasiou (ORCID: https://orcid.org/0000-0003-3378-6612)
- Kornélia Polyák (ORCID: https://orcid.org/0000-0002-5964-0382)
- Andrew H. Reiter (ORCID: https://orcid.org/0000-0003-1406-4913)
- Benedetto Diciaccio
- Triet M. Bui (ORCID: https://orcid.org/0000-0002-1092-9820)
- Madhu Lal‐Nag (ORCID: https://orcid.org/0000-0003-4924-6493)
- Myles A Brown (ORCID: https://orcid.org/0000-0002-8213-1658)
- Pierre Foidart (ORCID: https://orcid.org/0000-0003-4198-271X)
- Yijia Jiang (ORCID: https://orcid.org/0000-0002-0239-6999)
- Stephen C. Kales (ORCID: https://orcid.org/0000-0002-8702-5766)
- Xintao Qiu (ORCID: https://orcid.org/0000-0002-8560-7017)
- Evangelia K. Papachristou (ORCID: https://orcid.org/0000-0002-5835-2055)
- Marco Seehawer (ORCID: https://orcid.org/0000-0003-0440-6967)
- Ganesha Rai (ORCID: https://orcid.org/0000-0001-9763-9641)
- Jun Nishida (ORCID: https://orcid.org/0000-0001-5098-9361)
- Anton Simeonov (ORCID: https://orcid.org/0000-0002-4523-9977)
- Ajit Jadhav (ORCID: https://orcid.org/0000-0001-7955-1451)
- Henry W. Long (ORCID: https://orcid.org/0000-0001-6849-6629)
- Zheqi Li (ORCID: https://orcid.org/0000-0003-1213-640X)
- Jason S. Carroll (ORCID: https://orcid.org/0000-0003-3643-0080)
- Clive S. D’Santos (ORCID: https://orcid.org/0000-0003-3425-7288)
- Huang Xiao-Yun
- Rong Li (ORCID: https://orcid.org/0000-0001-7266-0241)
- Andriana Patmanidis
Institutions
- Broad Institute (US)
- National Institutes of Health (US)
- University of Cambridge (GB)
- Bridge University (SS)
- Dana-Farber Cancer Institute (US)
- Eli and Edythe Broad Foundation (US)
- National Center for Advancing Translational Sciences (US)
- Dana-Farber Brigham Cancer Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1016/j.celrep.2024.114991
- Citations
- 7
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- National Institutes of Health
- Ludwig Center at Harvard
- National Cancer Institute
- National Center for Advancing Translational Sciences