Non-Canonical HIF2 Accumulation in Breast Cancer Cells
- 1Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
- 2The BioMedChem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, Jana Matejki 21/23, 90-237 Lodz, Poland
- 3Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
Abstract
Metabolic reprogramming drives cancer aggressiveness. While hypoxia-inducible factor 1 (HIF1) is commonly associated with glycolysis regulation, the under-investigated HIF2 isoform may also modulate the metabolic profile of breast cancer. We investigated the role of non-canonical HIF2 activation in metabolic adaptation to nutrient availability by culturing MDA-MB-231 and MCF-7 cells under normoxia with varying glucose and glutamine concentrations. Using RNA interference, we downregulated HIF2 and analyzed HIF isoforms and metabolic targets (GLUT1, HK2, PKM2, PDK1) at the transcriptional and protein levels. We observed a new, non-canonical accumulation of HIF2 in MDA-MB-231 cells associated with glucose and glutamine restriction, a phenomenon absent in MCF-7 cells. In MDA-MB-231 cells, silencing HIF2A under standard conditions significantly decreased PDK1 mRNA expression. At the protein level, HIF2 downregulation altered metabolic targets in a context-dependent manner under nutrient restriction. Adding a hypoxia-mimetic (CoCl2) did not fully restore the protein expression patterns, suggesting that HIF2 accumulation may contribute to these context-dependent shifts. HIF2 downregulation decreased glycolytic efficiency under low-glucose conditions. Our findings suggest that HIF2 might modulate the metabolic plasticity of MDA-MB-231 cells through distinct changes in gene expression and post-translational mechanisms. This provides support for investigating the HIF2 isoform while studying breast cancer metabolism and considering it as a potential target for treating triple-negative breast cancer.
Related
- Low-dose doxorubicin drives caveolin-1 depended re-epithelialization of breast cancer cells as a mechanism of cancer plasticity
- 400 Proinflammatory and immune checkpoint responses in bystander tumor cells in an in vitro breast cancer model
- Primary-Tumor Transcriptomic Signatures Associated with Circulating Tumor Cells Status in Breast Cancer: From CTC-Negative Remodeling to CTC-Associated Metastatic Programs
- Extracellular adenosine triphosphate upregulates S100A4 expression and promotes the migration and invasion of breast cancer cells via P2Y2/SOX9 signaling
- Seesaw configuration of the ODC-OAZ1-AZIN1 axis governs sensitivity to polyamine-targeting inhibitors of breast cancer cells
BibTeX
@article{kozal2026noncanonical,
title = {{Non-Canonical HIF2 Accumulation in Breast Cancer Cells}},
author = {Karolina Kozal and Aleksandra Opitz and Monika Jarosiewicz and Michał Juszczak and Anna Krześlak},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209306},
url = {https://www.mdpi.com/1422-0067/27/20/9306},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Non-Canonical HIF2 Accumulation in Breast Cancer Cells
AU - Karolina Kozal
AU - Aleksandra Opitz
AU - Monika Jarosiewicz
AU - Michał Juszczak
AU - Anna Krześlak
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209306
UR - https://www.mdpi.com/1422-0067/27/20/9306
AB - Metabolic reprogramming drives cancer aggressiveness. While hypoxia-inducible factor 1 (HIF1) is commonly associated with glycolysis regulation, the under-investigated HIF2 isoform may also modulate the metabolic profile of breast cancer. We investigated the role of non-canonical HIF2 activation in metabolic adaptation to nutrient availability by culturing MDA-MB-231 and MCF-7 cells under normoxia with varying glucose and glutamine concentrations. Using RNA interference, we downregulated HIF2 and analyzed HIF isoforms and metabolic targets (GLUT1, HK2, PKM2, PDK1) at the transcriptional and protein levels. We observed a new, non-canonical accumulation of HIF2 in MDA-MB-231 cells associated with glucose and glutamine restriction, a phenomenon absent in MCF-7 cells. In MDA-MB-231 cells, silencing HIF2A under standard conditions significantly decreased PDK1 mRNA expression. At the protein level, HIF2 downregulation altered metabolic targets in a context-dependent manner under nutrient restriction. Adding a hypoxia-mimetic (CoCl2) did not fully restore the protein expression patterns, suggesting that HIF2 accumulation may contribute to these context-dependent shifts. HIF2 downregulation decreased glycolytic efficiency under low-glucose conditions. Our findings suggest that HIF2 might modulate the metabolic plasticity of MDA-MB-231 cells through distinct changes in gene expression and post-translational mechanisms. This provides support for investigating the HIF2 isoform while studying breast cancer metabolism and considering it as a potential target for treating triple-negative breast cancer.
SN - 1422-0067
ER -