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
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.
