A MYC-ZNF148-ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer
Mijeong Kim,
Manjot Singh,
Bum-Kyu Lee,
Moira Hibbs,
Kirsty Richardson,
Lesley Ellies,
Larissa Wintle,
Lisa M. Stuart,
Jenny Y. Wang,
Dominic C. Voon,
Pilar Blancafort,
Jianlong Wang,
Jonghwan Kim,
Peter J. Leedman,
Andrew J. Woo
Affiliations
Mijeong Kim
Department of Molecular Biosciences, The University of Texas at Austin
Manjot Singh
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia
Bum-Kyu Lee
Department of Biomedical Sciences, Cancer Research Center, University at Albany, State University of New York
Moira Hibbs
RPH Research Centre, Royal Perth Hospital
Kirsty Richardson
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia
Lesley Ellies
Division of Pharmacology and Toxicology, School of Biomedical Sciences, The University of Western Australia
Larissa Wintle
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia
Lisa M. Stuart
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia
Jenny Y. Wang
School of Medical Sciences, Faculty of Medicine and Health, University of Sydney
Dominic C. Voon
Institute for Frontier Science Initiative, Kanazawa University
Pilar Blancafort
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia
Jianlong Wang
Department of Medicine, Columbia Center for Human Development, Columbia Stem Cell Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center
Jonghwan Kim
Department of Molecular Biosciences, The University of Texas at Austin
Peter J. Leedman
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia
Andrew J. Woo
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia
Abstract The MYC proto-oncogene (MYC) is one of the most frequently overexpressed genes in breast cancer that drives cancer stem cell-like traits, resulting in aggressive disease progression and poor prognosis. In this study, we identified zinc finger transcription factor 148 (ZNF148, also called Zfp148 and ZBP-89) as a direct target of MYC. ZNF148 suppressed cell proliferation and migration and was transcriptionally repressed by MYC in breast cancer. Depletion of ZNF148 by short hairpin RNA (shRNA) and CRISPR/Cas9 increased triple-negative breast cancer (TNBC) cell proliferation and migration. Global transcriptome and chromatin occupancy analyses of ZNF148 revealed a central role in inhibiting cancer cell de-differentiation and migration. Mechanistically, we identified the Inhibitor of DNA binding 1 and 3 (ID1, ID3), drivers of cancer stemness and plasticity, as previously uncharacterized targets of transcriptional repression by ZNF148. Silencing of ZNF148 increased the stemness and tumorigenicity in TNBC cells. These findings uncover a previously unknown tumor suppressor role for ZNF148, and a transcriptional regulatory circuitry encompassing MYC, ZNF148, and ID1/3 in driving cancer stem cell traits in aggressive breast cancer.
