Abstract
Metabolic reprogramming becomes more and more important in tumor biology. Among various metabolic type, glucose metabolism represents as the major energy source and is often dysregulated in breast cancer. DAB2IP is widely reported to be a tumor suppressor and act as a scaffold protein to suppress tumor malignancy in breast cancer. Interesting, DAB2IP was also found to be a potential regulator in glucose uptake, however, the concrete mechanism is still not delineated. In this present research, we found DAB2IP could inhibited glucose uptake under hypoxia condition in breast cancer cells through suppressing HIF-1a signals. Mechanically, DAB2IP could interact with E3 ubiquitin ligase, STUB1, via its PER domain, thus triggering STUB1 mediated HIF-1a ubiquitylation and degradation, and finally inhibit glucose metabolism and tumor progression. Deleting PER domain could abrogate DAB2IP-related inhibitory effect of glucose uptake, intracellular ATP production and lactic acid production in breast cancer. These findings exhibit the biological role of DAB2IP in cancer-related glucose metabolism, and unveils a novel mechanism of DAB2IP in regulating STUB1-driven HIF-1a ubiquitylated degradation in breast cancer.