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.

RAS ID

47155

Document Type

Journal Article

Date of Publication

1-1-2022

Volume

11

Issue

1

Funding Information

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)

School

Centre for Precision Health / School of Medical and Health Sciences

Creative Commons License

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

Publisher

Nature

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

Download

Included in

Oncology Commons

Share

 
COinS
 

Link to publisher version (DOI)

10.1038/s41389-022-00435-1