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-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.

Claudin 6: Therapeutic prospects for tumours, and mechanisms of expression and regulation (Review)

“…After overexpression of CLDN6, negative feedback inhibited the expression of HIF-1α to decrease the metastasis of breast cancer ( 29 ). The downregulation of CLDN6 expression was positively correlated with lymph node metastasis in breast cancer ( 30 ).…”

CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers

“…The expression of CLDN6 is regulated by the degree of cell fusion and junctional maturation, as evidenced by the increase in expression with time and a high dependence upon plating density [8]. CLDN6 expression is also regulated by oxygen and estrogen, which are mediated by transcription factors such as HIF-1α [21,22] and Estrogen receptor α/β (Erα/β) [23,24], respectively. In the presence of tobacco smoke, CLDN6 is decreased in A549 and SAEC cells and mice lung tissues due to the interaction of HIF-1α and HIF-1α response element 1 (HRE1) at the CLDN6 promoter [21].…”

“…In the presence of tobacco smoke, CLDN6 is decreased in A549 and SAEC cells and mice lung tissues due to the interaction of HIF-1α and HIF-1α response element 1 (HRE1) at the CLDN6 promoter [21]. However, HIF-1α promotes CLDN6 transcription in hypoxic cultured breast cancer cells [22]. The two contrasting regulations of CLDN6 by HIF-1α may be related to the environment or tissue specificity, reflecting the complexity of protein regulation.…”

“…Studies have shown that CLDN6 inhibits the development and progression in some cancers such as breast cancer [22,24,[61][62][63], cervical cancer [56], and meningioma [64]. In hepatocellular cancer [50,65,66], gastric cancer [52,67], endometrial cancer [68,69], and ovarian cancer [70], CLDN6 has the opposite roles.…”

SUMOylation Wrestles With the Occurrence and Development of Breast Cancer

“…SENP1 may function by deSUMOylating related substrates. For example, a study found that SENP1 can deSUMOylate HIF-1α to enhance HIF-1α stabilization and ultimately promote breast cancer metastasis ( 66 ). Furthermore, SENP1 can deSUMOylate and regulate the protein activity and oncogenic function of the isomerase Pin1, which is an important regulator of cellular processes involving Pro-directed phosphorylation in breast cancer ( 67 ).…”