(533d) Palmitate Induced Desmoplakin Loss and Enhanced Migration of Breast Cancer Cell Mediated By the IRE1?-XBP1-ZEB1 Pathway

Elevated levels of the saturated fatty acid, palmitate (PA), have been linked to metastatic progression of cancer cells; however, the precise mechanism behind this connection is not well understood. The loss of cell adhesion proteins, such as desmoplakin (DSP), plays an important role in driving the transformation events of cancer cells to become metastatic. Our laboratory previously showed PA activated the IRE1α-XBP1 (inositol-requiring enzyme 1α-X-box binding protein 1) pathway, which is a branch of the endoplasmic reticulum (ER) stress response. Here, we investigated the role PA plays in the activation of the IRE1α-XBP1 pathway in promoting the loss of DSP in breast cancer cells. We found that treating a human breast cancer cell line, MDA-MB-231, with PA induced the loss of DSP and enhanced cell migration mediated by the IRE1α-XBP1 pathway. Furthermore, silencing DSP was sufficient to promote cell migration. We found that zinc finger E-box binding homeobox 1 (ZEB1) transcription factor functions as a direct transcriptional repressor of DSP and that PA increased the expression of ZEB1. CRISPR-Cas9 knockout of IRE1α abolished the PA-induced increase in ZEB1 expression, decrease in DSP levels, and cell migration in the breast cancer cells. Based on these findings, we propose that the loss of DSP and the increase in cell migration in breast cancer cells induced by PA is mediated by the IRE1α-XBP1-ZEB1 pathway.