LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway

Abstract

Epithelial-to-Mesenchymal Transition (EMT) is a key process contributing to the aggressiveness of cancer cells. EMT is triggered by activation of different transcription factors collectively known as EMT-TFs. Different cellular cues and cell signalling networks activate EMT at transcriptional and posttranscriptional level in different biological and pathological situations. Among them, overexpression of LOXL2 (lysyl oxidase-like 2) induces EMT independent of its catalytic activity. Remarkably, perinuclear/cytoplasmic accumulation of LOXL2 is a poor prognosis marker of squamous cell carcinomas and is associated to basal breast cancer metastasis by mechanisms no yet fully understood. Here, we report that overexpression of LOXL2 promotes its accumulation in the Endoplasmic Reticulum where it interacts with HSPA5 leading to activation of the IRE1-XBP1 signalling pathway of the ER-stress response. LOXL2-dependent IRE1-XBP1 activation induces the expression of several EMT-TFs: SNAI1, SNAI2, ZEB2 and TCF3 that are direct transcriptional targets of XBP1. Remarkably, inhibition of IRE1 blocks LOXL2-dependent upregulation of EMT-TFs thus hindering EMT induction.

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

“…Initial studies suggested that LOXL2 action on tumorigenesis and metastasis could be similar to that of LOX, thus related to its potential ECM crosslinking activity (8, 18, 19). Nevertheless, subsequent studies demonstrated an unconventional action of intracellular LOXL2 in invasion and metastasis (12, 17, 20–22), including induction of epithelial to mesenchymal transition (EMT), Snail1 stabilization (a key EMT transcription factor), and activation of the UPR pathway (23, 24). LOXL2/Snail1-mediated repression of E-cadherin and other epithelial genes contributes to the dedifferentiated and metastatic phenotype of squamous cell carcinomas and basal breast carcinoma cells, respectively (12, 20).…”

“…LOXL2/Snail1-mediated repression of E-cadherin and other epithelial genes contributes to the dedifferentiated and metastatic phenotype of squamous cell carcinomas and basal breast carcinoma cells, respectively (12, 20). Of note, LOXL2-dependent transcriptional repression and EMT induction in cell culture systems does not require its catalytic activity (12, 17, 24, 25), indicating that, at least, part of LOXL2 unconventional actions in cancer may not depend on ECM remodeling. To date, the implication on LOXL2 in tumorigenesis and metastasis rely on cell model systems with overexpression or knockdown of LOXL2.…”

The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance

“…Activation of IRE1 was dependent on the sequestering of GRP78 by LOXL2, which resulted in XBP1s‐dependent up‐regulation of Snail1, Snail2, Zeb2 and Tcf3 transcription factors. Inhibition of IRE1 RNase activity, by the small molecule inhibitor 4μ8c, reduced LOXL2‐mediated loss of E‐cadherin and blocked transition to a spindle morphology that is typical of cells post‐EMT [Cuevas et al., ]. These studies indicate that loss of IRE1 signalling should reduce the invasive and migratory capacity of cells by suppressing EMT.…”

The multiple roles of the unfolded protein response regulator IRE1α in cancer

“…In a different study of breast cancer, overexpression of lysyl oxidase‐like 2 triggered epithelial‐mesenchymal transition (EMT) in basal‐like breast carcinoma cell lines through the activation of IRE1α and subsequent XBP1 splicing. In these cells, XBP1 was shown to directly induce several EMT‐transcription factors such as SNAI1, ZEB2, and TCF3 . In MM, however, increased levels of the IRE1α‐XBP1 pathway are a survival mechanism that occurs in response to the stress of elevated antibody production and secretion.…”

“…In these cells, XBP1 was shown to directly induce several EMT-transcription factors such as SNAI1, ZEB2, and TCF3. 40 In MM, however, increased levels of the IRE1α-XBP1 pathway are a survival mechanism that occurs in response to the stress of elevated antibody production and secretion. In several studies of MM patients, hyperactivation of IRE1α-XBP1 signaling, or a high ratio spliced to unspliced XBP1 mRNA was again linked to poor prognosis.…”