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Journal of Experimental & Clinical Cancer Research

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01-12-2020 | Metastasis | Research

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

Authors: Yiyang Jia, Yantong Guo, Qiu Jin, Huinan Qu, Da Qi, Peiye Song, Xiaoli Zhang, Xinqi Wang, Wenhong Xu, Yuan Dong, Yingying Liang, Chengshi Quan

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

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.

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Title: A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis
Authors: Yiyang Jia
Yantong Guo
Qiu Jin
Huinan Qu
Da Qi
Peiye Song
Xiaoli Zhang
Xinqi Wang
Wenhong Xu
Yuan Dong
Yingying Liang
Chengshi Quan
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Metastasis
Breast Cancer
Breast Cancer
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-020-01547-5

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Abstract

Background

Methods

Results

Conclusions

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