A MYC-ZNF148-ID1/3 regulatory axis modulating cancer stem cell traits in aggressive breast cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 07, 2022
- Source ID
- 10.1038/s41389-022-00435-1
Entities
People
- Andrew J Woo
- BumâKyu Lee
- Dominic C. Voon
- Jenny Y. Wang
- Jianlong Wang
- Jonghwan Kim
- Kirsty Richardson
- Larissa Wintle
- Lesley Ellies
- Lisa M. Stuart
- Manjot Singh
- Mijeong Kim
- Moira Hibbs
- Peter J Leedman
- Pilar Blancafort
Organizations
- Cancer Council Australia
- Department of Health
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
- Royal Perth Hospital
- United States Department of Defense