Elevated uptake of saturated fatty acid palmitate is associated with metastatic progression of cancer cells; however, the precise signaling mechanism behind the phenomenon is unclear. The loss of cell adhesion proteins, such as desmoplakin (DSP), is a key driving event in the transformation of cancer cells to more aggressive phenotypes. Here we investigated the mechanism by which palmitate induces the loss of DSP in liver and breast cancer cells. We propose that palmitate activates the IRE1-XBP1 branch of the endoplasmic reticulum (ER) stress pathway to upregulate the ZEB transcription factor, leading to transcriptional repression of DSP. Using liver and breast cancer cells treated with palmitate, we found loss of DSP leads to increased cell migration independent of E-cadherin. We report that the ZEB family of transcription factors function as direct transcriptional repressors of DSP. CRISPR-mediated knockdown of IRE1 confirmed that the transcription of ZEB, loss of DSP, and enhanced migration in the presence of palmitate is dependent on the IRE1-XBP1 pathway. Additionally, by analyzing the somatic expression and copy number variation profiles of over 11,000 tumor samples, we corroborate our hypothesis and establish the clinical relevance of DSP loss via ZEB in human cancers. Implications: Provides mechanistic link on palmitate-induced activation of IRE1α to cancer cell migration.

中文翻译：

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棕榈酸酯诱导的 IRE1-XBP1-ZEB 信号抑制桥粒蛋白表达并促进癌细胞迁移

饱和脂肪酸棕榈酸酯的摄取增加与癌细胞的转移进展有关；然而，这一现象背后的确切信号机制尚不清楚。细胞粘附蛋白的丧失，如去粒斑蛋白 (DSP)，是癌细胞转化为更具攻击性表型的关键驱动事件。在这里，我们研究了棕榈酸酯诱导肝癌和乳腺癌细胞中 DSP 损失的机制。我们建议棕榈酸酯激活内质网 (ER) 应激通路的 IRE1-XBP1 分支以上调 ZEB 转录因子，从而导致 DSP 的转录抑制。使用棕榈酸酯处理的肝癌和乳腺癌细胞，我们发现 DSP 的丢失导致细胞迁移增加，而与 E-钙粘蛋白无关。我们报告 ZEB 家族的转录因子作为 DSP 的直接转录阻遏物起作用。CRISPR 介导的 IRE1 敲低证实了 ZEB 的转录、DSP 的丢失和棕榈酸酯存在下的迁移增强依赖于 IRE1-XBP1 通路。此外，通过分析超过 11,000 个肿瘤样本的体细胞表达和拷贝数变异谱，我们证实了我们的假设并确定了人类癌症中通过 ZEB 丢失 DSP 的临床相关性。启示：提供棕榈酸酯诱导的 IRE1α 激活与癌细胞迁移的机制联系。通过分析超过 11,000 个肿瘤样本的体细胞表达和拷贝数变异谱，我们证实了我们的假设并确定了人类癌症中通过 ZEB 损失的 DSP 的临床相关性。启示：提供棕榈酸酯诱导的 IRE1α 激活与癌细胞迁移的机制联系。通过分析超过 11,000 个肿瘤样本的体细胞表达和拷贝数变异谱，我们证实了我们的假设并确定了人类癌症中通过 ZEB 损失的 DSP 的临床相关性。启示：提供棕榈酸酯诱导的 IRE1α 激活与癌细胞迁移的机制联系。