A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis

Abstract

Background We have previously described CLDN6 as a tumor suppressor gene in breast cancer. Here, a new finding is that CLDN6 was upregulated under hypoxia, a commonly recognized factor that promotes tumor metastasis. In this study, we aim to explain this confusing finding and delineate the role of CLDN6 in the breast cancer metastasis induced by hypoxia. Methods RNAi and ChIP assays were used to confirm that CLDN6 is transcriptional regulated by HIF-1 alpha. mRNA seq and KEGG analysis were performed to define the downstream pathways of CLDN6. The roles of the CLDN6/SENP1/HIF-1 alpha signaling on tumor metastasis were evaluated by function experiments and clinical samples. Finally, the possible transcription factor of SENP1 was suspected and then validated by ChIP assay. Results We demonstrated a previously unrecognized negative feedback loop exists between CLDN6 and HIF-1 alpha. CLDN6 was transcriptionally up-regulated by HIF-1 alpha under hypoxia. On the other hand, in cytoplasm CLDN6 combines and retains beta-catenin, a transcription factor of SENP1, causing beta-catenin degradation and preventing its nuclear translocation. This process reduced SENP1 expression and prevented the deSUMOylation of HIF-1 alpha, ultimately leading to HIF-1 alpha degradation and breast cancer metastasis suppression. Conclusions Our data provide a molecular mechanistic insight indicating that CLDN6 loss may lead to elevated HIF-1 alpha-driven breast cancer metastasis in a SUMOylation-dependent manner.