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.

中文翻译：

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SUMOylation依赖的HIF-1α/ CLDN6负反馈缓解了低氧诱导的乳腺癌转移。

背景技术我们先前已经将CLDN6描述为乳腺癌中的肿瘤抑制基因。在这里，一个新发现是CLDN6在缺氧条件下被上调，缺氧条件是公认的促进肿瘤转移的因子。在这项研究中，我们旨在解释这一令人困惑的发现，并描述CLDN6在低氧引起的乳腺癌转移中的作用。方法采用RNAi和ChIP分析法确认CLDN6受HIF-1α转录调控。进行mRNA seq和KEGG分析以定义CLDN6的下游途径。通过功能实验和临床样本评估了CLDN6 / SENP1 /HIF-1α信号传导在肿瘤转移中的作用。最后，怀疑了SENP1的可能转录因子，然后通过ChIP测定法对其进行了验证。结果我们证明了CLDN6和HIF-1α之间存在一个以前无法识别的负反馈回路。在缺氧条件下，CLIF6被HIF-1α转录上调。另一方面，CLDN6在细胞质中结合并保留SENP1的转录因子β-catenin，导致β-catenin降解并阻止其核易位。这个过程减少了SENP1表达并阻止了HIF-1α的去SUMOylation，最终导致HIF-1α降解和乳腺癌转移抑制。结论我们的数据提供了分子机制的见解，表明CLDN6的缺失可能以SUMOylation依赖的方式导致HIF-1α驱动的乳腺癌转移升高。SENP1的转录因子，导致β-catenin降解并阻止其核易位。该过程降低了SENP1的表达并阻止了HIF-1α的去SUMOylation，最终导致HIF-1α降解和乳腺癌转移抑制。结论我们的数据提供了分子机制的见解，表明CLDN6的缺失可能以SUMOylation依赖的方式导致HIF-1α驱动的乳腺癌转移升高。SENP1的转录因子，导致β-catenin降解并阻止其核易位。这个过程减少了SENP1表达并阻止了HIF-1α的去SUMOylation，最终导致HIF-1α降解和乳腺癌转移抑制。结论我们的数据提供了分子机制的见解，表明CLDN6的缺失可能以SUMOylation依赖的方式导致HIF-1α驱动的乳腺癌转移升高。