RHBDF1 promotes PERK expression through the JNK/FoxO3 pathway in breast cancer cells

Human rhomboid family-1 ( <i>RHBDF1</i>) gene is recognized as an oncogene involved in breast cancer development. Previous studies have indicated that RHBDF1 contributes significantly to endoplasmic reticulum (ER) protein homeostasis by stabilizing the binding immunoglobulin protein (BiP) and promoting the unfolded protein response (UPR). Here, we report a relationship between RHBDF1 and the ER stress sensors PERK, IRE1, and ATF6. We show that RHBDF1 deficiency in breast cancer cells results in decreased levels of PERK, pPERK, and peIF2α. These protein levels can be restored in RHBDF1-deficient breast cancer cells by artificial overexpression of RHBDF1 but not IRE1 or ATF6. Additionally, we show that the transcription factor FoxO3 is essential for the RHBDF1-mediated production of PERK. Subsequent analysis reveals that RHBDF1 activates JNK, which causes FoxO3 to translocate into the cell nucleus. These findings demonstrate that RHBDF1 supports the UPR by upregulating the PERK/peIF2α pathway via the JNK/FoxO3 axis and that the functions of RHBDF1 are essential for preserving the homeostasis of ER proteins.