LOXL2 in Cancer: A Two-Decade Perspective

Abstract

Lysyl Oxidase Like 2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises five lysine tyrosylquinone (LTQ)-dependent copper amine oxidases in humans. In 2003, LOXL2 was first identified as a promoter of tumour progression and, over the course of two decades, numerous studies have firmly established its involvement in multiple cancers. Extensive research with large cohorts of human tumour samples has demonstrated that dysregulated LOXL2 expression is strongly associated with poor prognosis in patients. Moreover, investigations have revealed the association of LOXL2 with various targets affecting diverse aspects of tumour progression. Additionally, the discovery of a complex network of signalling factors acting at the transcriptional, post-transcriptional, and post-translational levels has provided insights into the mechanisms underlying the aberrant expression of LOXL2 in tumours. Furthermore, the development of genetically modified mouse models with silenced or overexpressed LOXL2 has enabled in-depth exploration of its in vivo role in various cancer models. Given the significant role of LOXL2 in numerous cancers, extensive efforts are underway to identify specific inhibitors that could potentially improve patient prognosis. In this review, we aim to provide a comprehensive overview of two decades of research on the role of LOXL2 in cancer.

Keywords: LOXL2; human tumour sample; mouse models; regulation; targets; tumour progression.

Figure 1

Frequency of gene copy alterations detected in LOXL2 locus among all tumour types. Red bars (left) correspond to the frequency of gene amplification and green bars (right) to deep deletions.

Figure 2

Frequency of point mutations detected in LOXL2 gene among all tumour types.

Figure 3

LOXL2 regulation. Left side, LOXL2 gene expression is regulated in different cancer scenarios by three well characterised signalling pathways (extracellular ATP, hypoxia, and ECM remodelling) that impinge on different transcriptional factors, including HIF1α, HIF1β, HIF2α, and lysine demethylases KDM4B and KDM4C. The proto-oncogene c-FOS controls LOXL2 expression through the Wnt7/9-ZEB1/2 axis. Deubiquitinase ZRANB1 stabilises the transcription factor SP1. Right bottom cytoplasm side, several miRNAs act through the LOXL2 3’UTR mRNA region to downregulate its gene expression. Long noncoding RNAs (lncRNA) and circular RNAs (circRNA) counteracting the miRNAs (green boxes) are marked in grey. Right upper cytoplasm side, LOXL2 is directed to the ubiquitin–proteasome pathway by the interaction with TRIM44. LOXL2 is phosphorylated by LAST1 with unknown functional consequences. Upper right side, LOXL2 in the extracellular compartment undergoes proteolytic processing by PACE4 and factor Xa proteases, and secreted EGFL7 inhibits LOXL2 catalytic activity. Extracellular LOXL2 also interacts with HSP90, although the functional consequences of this interaction are unknown. Nuclear LOXL2 is negatively regulated by the lncRNA GATA6-AS. The question mark (?) means that the functional consequences of LOXL2 phosphorylation are unknown.

Figure 4

Targets of secreted LOXL2. LOXL2 provokes ECM remodelling, activating the FAK signalling pathway in fibroblasts and tumour cells. Additionally, it stimulates the AKT and ERK signalling pathways specifically in tumour cells. LOXL2 oxidises PDGFRβ, enhancing ERK signalling in fibroblasts, and increases the secretion of lymphangiogenic factors (VEGFC and SDF-1α). In distant organs, secreted or exosomal LOXL2 stimulates the formation of premetastatic niche.

Figure 5

Intracellular targets of LOXL2. LOXL2 can influence numerous pro-tumorigenic actions in different tumour contexts by interacting with various effectors located in the plasma membrane (i.e., ERBB2 receptor and ITGA5/ITGB1 integrins) or the cytoplasm (FAK, ezrin, VIM, AKT, MARKSL1, ERK1/2, IQGAP1, and ALDOA), thereby affecting diverse cellular processes. The interaction of LOXL2 and HSPA5/BiP in the ER leads to activation of the transcription factor XBP1, which upregulates several EMT-TFs. Red arrows indicate positive regulation, and red blunt-end arrows signify negative regulation exerted by LOXL2 on the indicated targets. The final functional processes altered by LOXL2 action are marked in grey.

Figure 6

Nuclear targets of LOXL2. In different tumour scenarios, nuclear LOXL2 exerts its pro-tumorigenic roles by interacting with various transcription factors (SNAI1, E47, KLF4 and GATA6), modifying histone marks (H3K4me3 and H3K36ac), and upregulating the expression of different effectors (HIF1, SMO/GLI, and RAMP3). The downregulation of cell polarity complex genes (LLGL2, CLDN1) and upregulation of antiapoptotic genes (BIRC3 and MDM2) are mediated by unknown transcription factors. Red arrows denote positive regulation and red blunt-end arrows signify negative regulation exerted by LOXL2 on the indicated targets. Final functional processes altered by LOXL2 action are marked in grey. The question mark (?) means that the direct LOXL2 target or the functional consequences of an LOXL2 action are unknown.

Figure 7

Strategies used to block LOXL2 action on tumour progression. The generation of anti-LOXL2 antibodies, optimisation of copper chelators, search for natural products capable of blocking the expression of LOXL2, or the development of small molecules designed to inhibit the catalytic activity of LOXL2 are different approaches currently being developed with the ultimate goal of interfering with the pro-tumorigenic action of LOXL2.