Key Takeaways & Executive Findings
- •• RHBDF1 deficiency reduces PERK, pPERK, and peIF2α levels in breast cancer cells, which can be restored by RHBDF1 overexpression but not by IRE1 or ATF6. • RHBDF1 activates the JNK pathway, leading to nuclear translocation of FoxO3, which is essential for PERK expression. • The study establishes a novel RHBDF1-JNK-FoxO3-PERK axis in the unfolded protein response, highlighting RHBDF1's role in ER protein homeostasis. • These findings suggest that targeting RHBDF1 or its downstream pathway could be a potential therapeutic strategy for breast cancer.
Abstract
Human rhomboid family-1 (RHBDF1) 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.
1. Introduction
Cancer cells possess an unfolded protein response (UPR) system for survival and growth [1-3] and are resistant to chemotherapy [3]. Cancer cells under endoplasmic reticulum (ER) stress activate the UPR, which is composed of the binding immunoglobulin protein (BiP) and three major branch pathways, including the PRKR-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) pathways [4–7]. As a primary ER stress sensor, PERK plays a major role in the maintenance of ER protein homeostasis. Under ER stress conditions, PERK becomes dimerized and autophosphorylated, which leads to the phosphorylation of the eukaryotic translation initiation factor 2 subunit (eIF2α) [8,9]. Phosphor-eIF2α temporarily halts global protein synthesis to reduce the ER burden or activate the translation of activating translation factor 4 (ATF4), which in turn activates the apoptotic transcription factor C/EBP homologous protein (CHOP) to induce apoptosis [5,9–11]. Thus, delineating the molecular mechanism underlying PERK production in cancer cells is important.
Human rhomboid family 1 protein (RHBDF1), also known as inactivated rhomboid 1 (iRhom1), is an ER-resident membrane protein that plays a substantial role in cancer development [12,13]. Despite the lack of protease activity, the RHBDF1 protein has been found to participate critically in many important biological processes, including stabilizing hypoxia-inducible factor-1α (HIF-1α) in cancer cells under hypoxic conditions [14] and promoting activator protein 1 (AP-1)-activated endothelial-mesenchymal transition (EndMT) by activating the c-Jun N-terminal kinase (JNK) pathway [15]. RHBDF1 expression is diminished in normal breast tissues but highly elevated in tumor tissues, which is strongly correlated with increased disease progression, metastasis, poor prognosis, and poor response to chemotherapy [14,16–21]. Additionally, RHBDF1 plays a key role in maintaining ER protein homeostasis by stabilizing the BiP protein [22]. Therefore, investigating the involvement of the RHBDF1 protein in the regulation of the functional components of the UPR, namely, the PERK, IRE1, and ATF6 pathways, is worthwhile.
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SungJu Ryu, Hui Long, Xiaojing Quan, UnChol Kim, Wenwen Zhao, Yuanyuan Song, Luyuan Li, Zhisong Zhang (2026). RHBDF1 promotes PERK expression through the JNK/FoxO3 pathway in breast cancer cells. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024163
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Frequently Asked Questions
What is the role of RHBDF1 in breast cancer cells?
RHBDF1 is an oncogene that promotes breast cancer development by supporting the unfolded protein response (UPR) and maintaining ER protein homeostasis. It specifically upregulates the PERK/peIF2α pathway via the JNK/FoxO3 axis.
How does RHBDF1 regulate PERK expression?
RHBDF1 activates the JNK pathway, which leads to the nuclear translocation of the transcription factor FoxO3. FoxO3 then promotes the expression of PERK, thereby enhancing the PERK/peIF2α branch of the UPR.
What are the downstream effects of RHBDF1 deficiency?
RHBDF1 deficiency in breast cancer cells results in decreased levels of PERK, pPERK, and peIF2α, impairing the UPR and potentially affecting cell survival under ER stress.
Could RHBDF1 be a therapeutic target for breast cancer?
Yes, since RHBDF1 is elevated in breast cancer and essential for UPR-mediated survival, targeting RHBDF1 or its downstream JNK/FoxO3/PERK pathway could be a potential therapeutic strategy.
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