Abstract
Different cancer types as well as many other diseases are caused by aberrant activation of the canonical Wnt signal transduction pathway, and it is especially implicated in the development and progression of colorectal cancer (CRC). The main effector protein of the canonical Wnt signaling cascade is β-catenin, which binds to the T- cell factor/lymphoid enhancer factor (TCF/LEF) and triggers the activation of Wnt target genes. Here, we identify the serine protease High-Temperature Requirement A1 (HTRA1) as a novel component of the canonical Wnt pathway. We show that the HTRA1 protein inhibits the Wnt/β-catenin signaling, in both paracrine and autocrine manners, and affects the expression of several Wnt target genes. Moreover, HTRA1 forms a complex with β-catenin and reduces the proliferation rates of cells. Taken together, our findings indicate that HTRA1 functions as a novel suppressor of the canonical Wnt signaling pathway.
Highlights
As several studies have shown that the Wnt cascade and TGF-β signaling crosstalk and that High-Temperature Requirement A1 (HTRA1) may function through TGF-β, we examined the effect of TGF-β on HTRA1-affected Wnt target genes
We show that, in accordance with its tumor suppressive activity, HTRA1 acts as an inhibitor of the canonical Wnt cascade by down-regulating the Wnt signal and the expression of specific Wnt target genes
A number of studies have discussed the differences in the expression of Wnt target genes and have shown that c-myc can be differentially expressed as compared with other Wnt target genes that are dependent on the cell cycle[29], chronological expression[30], and whose expression levels are dependent on promoter conformation[31]
Summary
Several publications link the HTRA1 gene to tumorigenesis, since it has been found to be down-regulated in many tumors such as prostate cancer, medulloblastoma[18], ovarian cancer[19], melanoma[20], lung carcinoma[21], and mesothelioma[22]. Several studies indicate that HTRA1 expression is lower in estrogen-receptor(ER)-negative tumors and that down-regulation of HTRA1 is significantly correlated with a higher grade of breast carcinoma[23]. We show that HTRA1 interacts with β-catenin and that its effect on the Wnt signal is mediated through β-catenin degradation by the proteasome. These findings indicate that HTRA1 may be a novel regulator involved in controlling the canonical Wnt cascade
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