DAB2IP inhibits glucose uptake by modulating HIF-1α ubiquitination under hypoxia in breast cancer

• Published in: Oncogenesis (New York, NY) Vol. 13; no. 1; pp. 20 - 13
• Main Authors: Dong, Hongliang, Jia, Weiyi, Meng, Weijian, Zhang, Rui, Qi, Zhihong, Chen, Zhuo, Xie, Sophia, Min, Jiang, Liu, Liang, Shen, Jie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.06.2024; Nature Publishing Group
• Subjects: 13/105; 13/109; 13/51; 13/89; 14/32; 38/70; 38/77; 59/78; 631/67/1347; 631/67/2327; 64/60; 82/1; 82/58; 96/63; Acid production; Apoptosis; Breast cancer; Cell Biology; Glucose; Glucose metabolism; Human Genetics; Hypoxia; Hypoxia-inducible factor 1a; Internal Medicine; Malignancy; Medicine; Medicine & Public Health; Metabolic pathways; Metabolism; Oncology; Tumor suppressor genes; Tumors; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 2157-9024; 2157-9024
• DOI: 10.1038/s41389-024-00523-4

Metabolic reprogramming has become increasingly important in tumor biology research. The glucose metabolic pathway is a major energy source and is often dysregulated in breast cancer. DAB2IP is widely reported to be a tumor suppressor that acts as a scaffold protein to suppress tumor malignancy in breast cancer. Interestingly, DAB2IP has also been found to be a potential regulator of glucose uptake; however, the exact mechanism remains unclear. In this study, we found that DAB2IP inhibited glucose uptake under hypoxia conditions in breast cancer cells by suppressing HIF-1α signals. Mechanically, DAB2IP interacted with the E3 ubiquitin ligase STUB1 via its PER domain, thus triggering STUB1 mediated HIF-1α ubiquitylation and degradation, and inhibit glucose metabolism and tumor progression. Deleting the PER domain abrogated the DAB2IP-related inhibitory effects on glucose uptake, intracellular ATP production, and lactic acid production in breast cancer cells. These findings elucidate the biological roles of DAB2IP in cancer-related glucose metabolism as well as a novel mechanism by which STUB1-driven HIF-1α ubiquitylated degradation is regulated in breast cancer.