Cell Reports (Dec 2024)
ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer
- Benedetto DiCiaccio,
- Marco Seehawer,
- Zheqi Li,
- Andriana Patmanidis,
- Triet Bui,
- Pierre Foidart,
- Jun Nishida,
- Clive S. D’Santos,
- Evangelia K. Papachristou,
- Malvina Papanastasiou,
- Andrew H. Reiter,
- Xintao Qiu,
- Rong Li,
- Yijia Jiang,
- Xiao-Yun Huang,
- Anton Simeonov,
- Stephen C. Kales,
- Ganesha Rai,
- Madhu Lal-Nag,
- Ajit Jadhav,
- Myles Brown,
- Jason S. Carroll,
- Henry W. Long,
- Kornelia Polyak
Affiliations
- Benedetto DiCiaccio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Marco Seehawer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Zheqi Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Andriana Patmanidis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Triet Bui
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Pierre Foidart
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Jun Nishida
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Clive S. D’Santos
- Cambridge Research Institute, University of Cambridge, Cambridge, UK
- Evangelia K. Papachristou
- Cambridge Research Institute, University of Cambridge, Cambridge, UK
- Malvina Papanastasiou
- The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA
- Andrew H. Reiter
- The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA
- Xintao Qiu
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Rong Li
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Yijia Jiang
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Xiao-Yun Huang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Anton Simeonov
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
- Stephen C. Kales
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
- Ganesha Rai
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
- Madhu Lal-Nag
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
- Ajit Jadhav
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
- Myles Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Jason S. Carroll
- Cambridge Research Institute, University of Cambridge, Cambridge, UK
- Henry W. Long
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Kornelia Polyak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Ludwig Center at Harvard, Boston, MA 02115, USA; Corresponding author
- Journal volume & issue
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Vol. 43,
no. 12
p. 114991
Abstract
Summary: 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.
