Abstract
The lysyl oxidase (LOX) family is closely related to the progression of glioma. To ensure the clinical significance of LOX family in glioma, The Cancer Genome Atlas (TCGA) database was mined and the analysis indicated that higher LOXL1 expression was correlated with more malignant glioma progression. The functions of LOXL1 in promoting glioma cell survival and inhibiting apoptosis were studied by gain- and loss-of-function experiments in cells and animals. LOXL1 was found to exhibit antiapoptotic activity by interacting with multiple antiapoptosis modulators, especially BAG family molecular chaperone regulator 2 (BAG2). LOXL1-D515 interacted with BAG2-K186 through a hydrogen bond, and its lysyl oxidase activity prevented BAG2 degradation by competing with K186 ubiquitylation. Then, we discovered that LOXL1 expression was specifically upregulated through the VEGFR-Src-CEBPA axis. Clinically, the patients with higher LOXL1 levels in their blood had much more abundant BAG2 protein levels in glioma tissues. Conclusively, LOXL1 functions as an important mediator that increases the antiapoptotic capacity of tumor cells, and approaches targeting LOXL1 represent a potential strategy for treating glioma. In addition, blood LOXL1 levels can be used as a biomarker to monitor glioma progression.
Highlights
We found that patients with the low expression of lysyl oxidase (LOX) family coding genes, especially LOXL1 and LOXL4, survived longer than those with high expression of LOXL1 and LOXL4, using the best expression cutoff (Fig. 1a)
We found that LOX family proteins, especially LOXL1, can protect glioma cells from anoikis and ionizing radiation (IR) stresses, rendering cells resistant to apoptosis
LOXL1 is upregulated by the VEGFR-Src-CEBPA axis in suspended glioma cells, and LOXL1 and BAG family molecular chaperone regulator 2 (BAG2) proteins can interact in glioma cells, preventing BAG2-K186 ubiquitylation depending on LOXL1 enzymatic activity and stabilizing BAG2 to promote cell survival (Fig. 6k)
Summary
LOXs have many important biological functions, including the regulation of cell differentiation, mobility, migration and gene expression [6]. Recent studies have shown that LOXs expressions are increased under hypoxic conditions in malignant tumors, including esophageal cancer, colorectal tissue cancer, bladder cancer and head and neck cancer, and that they function in promoting tumor metastasis [7,8,9]. The lncRNA, LOXL1-AS, was required for maintaining mesenchymal characteristics of glioblastoma via NF-κB pathway [18] It is still elusive how LOXL1 is upregulated and exerts antiapoptotic function by directly forming an axis with other proteins during glioma progression. LOXL1 stabilized BAG2 by blocking K186 ubiquitination, rendering glioma cells resistant to apoptosis in nonadherent conditions. Our data suggest that LOXL1 can be a potential biomarker for guiding the clinical treatment of glioma, and the development of new drugs targeting LOXL1 may improve the curative efficacy and prolong survival in glioma patients
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