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

Authors

Mijeong Kim
Manjot Singh, Edith Cowan UniversityFollow
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, Edith Cowan UniversityFollow

Document Type

Journal Article

Publication Title

Oncogenesis

Volume

11

Issue

1

Publisher

Nature

School

Centre for Precision Health / School of Medical and Health Sciences

RAS ID

47155

Funders

Royal Perth Hospital Medical Research Foundation (AJW) / Cancer Council of Western Australia (WA) (AJW) / Department of Health, Government of WA (AJW) Walk for Women’s Cancer Gift (AJW) / Breast cancer research in JW laboratory was supported by Department of Defense (BC200469)

Comments

Kim, M., Singh, M., Lee, B. K., Hibbs, M., Richardson, K., Ellies, L., ... & Woo, A. J. (2022). A MYC-ZNF148-ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer. Oncogenesis, 11, Article 60. https://doi.org/10.1038/s41389-022-00435-1

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.

DOI

10.1038/s41389-022-00435-1

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.