Abstract
The inositol-requiring enzyme 1α (IRE1α) is an endoplasmic reticulum (ER)-resident transmembrane protein and senses cellular unfolded/misfolded proteins. Upon activation, IRE1α removes a 26-bp nucleotide from the mRNA encoding X-box binding protein (XBP) 1 to generate a spliced active form of this transcription factor (XBP1s). Though IRE1α is implicated in development of cancer, the role and underlying mechanism remain unclear. Here, we demonstrate that IRE1α regulates colon cancer cell metastasis through regulating the expression of fibronectin-1 (FN1). We found that knockdown of IRE1α inhibited colon cancer cell migration and invasion in vitro and metastasis in vivo. Knockdown of IRE1α decreased the formation of XBP1s and attenuated the expression of FN1, leading to inhibition of phosphorylation of Src and FAK and inactivation the downstream effector GTPases including RhoA, Rac1 and CDC42. Addition of exogenous FN1 reversed Src/FAK phosphorylation and cell migration inhibited by IRE1α knockdown. We found that XBP1s bound FN1 promoter and acted as a transcription factor to initiate FN1 expression. Our results suggest that IRE1α modulates metastatic potential of colon cancer cells through regulating the expression of FN1.
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