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
Conclusions
Our data provide a molecular mechanistic insight indicating that CLDN6 loss may lead to elevated HIF-1α-driven breast cancer metastasis in a SUMOylation-dependent manner.
Methods
RNAi and ChIP assays were used to confirm that CLDN6 is transcriptional regulated by HIF-1α. mRNA seq and KEGG analysis were performed to define the downstream pathways of CLDN6. The roles of the CLDN6/SENP1/HIF-1α 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-1α. CLDN6 was transcriptionally up-regulated by HIF-1α under hypoxia. On the other hand, in cytoplasm CLDN6 combines and retains β-catenin, a transcription factor of SENP1, causing β-catenin degradation and preventing its nuclear translocation. This process reduced SENP1 expression and prevented the deSUMOylation of HIF-1α, ultimately leading to HIF-1α degradation and breast cancer metastasis suppression. Conclusions: Our data provide a molecular mechanistic insight indicating that CLDN6 loss may lead to elevated HIF-1α-driven breast cancer metastasis in a SUMOylation-dependent manner.