A feedback mechanism between E3 ligase RNF122 and HIF-1α inhibits aggressive behavior in breast cancer.

The low oxygen tension frequently found in tumors drives the expression of hypoxia-inducible factors (HIFs), thereby supporting rapid cancer cell proliferation and metastasis. Therefore, the prolonged expression of HIF-1α, the master regulator of the adaptation to hypoxia, is a crucial protective mechanism for solid tumor progression. Here we report that RNF122, the novel E3 ligase of HIF-1α, is a hypoxia responsive gene. Importantly, loss of RNF122 dramatically promoted breast cancer cell migration, invasion, and metastasis. In the presence of hypoxia, HIF-1α transcriptionally activates the expression of RNF122, which in turn directly interacts with HIF-1α in the cytoplasm, promoting its degradation through K27-linked polyubiquitination. Consequently, RNF122 suppresses the transcriptional activity of HIF-1α and its target gene expression, thereby inhibiting the glucose metabolism and angiogenesis of breast cancer cells under hypoxic condition. Clinically, copy number loss of RNF122 occurs in 39% of breast cancer patients, and the level of RNF122 is positively correlated with increased overall survival. Taken together, our findings discovered a negative feedback loop between RNF122 and HIF-1α that inhibits hypoxia-mediated tumorigenic activity, revealing a novel mechanism by which neoplastic cells sustain HIF-1α-dependent malignancy under hypoxic condition in RNF122-negative breast cancers.