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

doi:10.1038/s41389-022-00435-1

A MYC-ZNF148-ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer

Oncogenesis. 2022 Oct 7;11(1):60. doi: 10.1038/s41389-022-00435-1.

Authors

Mijeong Kim¹, Manjot Singh^{2

3}, Bum-Kyu Lee⁴, Moira Hibbs⁵, Kirsty Richardson², Lesley Ellies⁶, Larissa Wintle², Lisa M Stuart², Jenny Y Wang⁷, Dominic C Voon^{8

9}, Pilar Blancafort^{2

10

11}, Jianlong Wang¹², Jonghwan Kim¹, Peter J Leedman¹³, Andrew J Woo^{14

15

16}

Affiliations

¹ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.
² Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Perth, WA, 6000, Australia.
³ Centre for Precision Health, Edith Cowan University, Joondalup, WA, 6027, Australia.
⁴ Department of Biomedical Sciences, Cancer Research Center, University at Albany, State University of New York, Rensselaer, NY, 12144, USA.
⁵ RPH Research Centre, Royal Perth Hospital, Perth, WA, 6000, Australia.
⁶ Division of Pharmacology and Toxicology, School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6000, Australia.
⁷ School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia.
⁸ Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, 920-1192, Japan.
⁹ Cancer Research Institute, Kanazawa University, Kanazawa, 920-1192, Japan.
¹⁰ School of Human Sciences, The University of Western Australia, Perth, WA, 6000, Australia.
¹¹ The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
¹² Department of Medicine, Columbia Center for Human Development, Columbia Stem Cell Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, 10032, USA.
¹³ Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Perth, WA, 6000, Australia. peter.leedman@perkins.org.au.
¹⁴ Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Perth, WA, 6000, Australia. andrew.j.woo@uwa.edu.au.
¹⁵ Centre for Precision Health, Edith Cowan University, Joondalup, WA, 6027, Australia. andrew.j.woo@uwa.edu.au.
¹⁶ School of Medical and Health Sciences, Edith Cowan University, Perth, WA, 6000, Australia. andrew.j.woo@uwa.edu.au.

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.

Abstract

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