ZBTB1 Regulates Glycolysis and Chemotherapy Resistance Through Interacting with c-Myc in Triple Negative Breast Cancer.

Background/

Objectives

Our previous study identified ZBTB1 as a novel tumor suppressor in estrogen receptor-positive (ER+) breast cancer. Moreover, The Cancer Genome Atlas (TCGA) data analysis showed a much lower level of ZBTB1 in triple-negative breast cancer than in ER+ breast cancer. Triple negative breast cancer (TNBC) lacks effective targeted therapies and largely depends on chemotherapy, while chemotherapy resistance remains a major clinical challenge. This study aimed to explore the role of ZBTB1 in TNBC progression and chemotherapy resistance.

Methods

We performed clinical survival analysis, in vitro and in vivo functional experiments, mass spectrometry screening, and mechanistic validation in TNBC and Adriamycin-resistant TNBC cells.

Results

We found that ZBTB1 protein is downregulated in TNBC and this downregulation correlates with shorter patient survival. ZBTB1 regulates glycolysis and chemotherapy resistance in TNBC cells. Mechanistically, ZBTB1 interacts with c-Myc and suppresses its transcriptional activity in MDA-MB-231 and MDA-MB-453 but not in Adriamycin-resistant cells (MDA-MB-231/ADR and MDA-MB-453/ADR). LncRNA SAP30L-AS1 is required for maintaining the ZBTB1-c-Myc interaction in TNBC cells. SAP30L-AS1 is significantly depleted in Adriamycin-resistant cells, which disrupts the binding between ZBTB1 and c-Myc. Functional validation revealed that SAP30L-AS1 modulates glycolysis and chemotherapy resistance in TNBC cells in a ZBTB1-dependent manner.

Conclusions

Collectively, our data indicate the key role of ZBTB1 in TNBC and ZBTB1 may serve as a novel approach for TNBC treatments.