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

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.

Automated summary

In this study, researchers identified ZNF148 as a direct target of MYC in breast cancer. ZNF148 suppressed cell proliferation and migration and was transcriptionally repressed by MYC. Depletion of ZNF148 increased triple-negative breast cancer (TNBC) cell proliferation and migration. Mechanistically, ZNF148 was found to transcriptionally repress ID1 and ID3 expression, resulting in inhibition of cancer stem cell traits and plasticity. These findings uncover a previously unknown tumor suppressor role for ZNF148 and reveal a transcriptional regulatory circuitry involving MYC, ZNF148, and ID1/3 in driving aggressive breast cancer.