Visinin-like 1, a novel target gene of the Wnt/β-catenin signaling pathway, is involved in apoptosis resistance in colorectal cancer

Background: Abnormal activation of Wnt/β-catenin signaling is associated with various aspects of cancer development. This study explored the roles of novel target genes of the Wnt/β-catenin signaling pathway in cancer cells.

Methods: Using the haploid chronic myelogenous leukemia cell line HAP1, RNA sequencing (RNA-seq) was performed to identify genes whose expression was increased by APC disruption and reversed by β-catenin knockdown (KD). The regulatory mechanism and function of one of the candidate genes was investigated in colorectal cancer (CRC) cells.

Results: In total, 64 candidate genes whose expression was regulated by Wnt/β-catenin signaling were identified. Of these candidate genes, the expression levels of six were reduced by β-catenin KD in HCT116 CRC cells in our previous microarray. One of these genes was Visinin-like 1 (VSNL1), which belongs to the neuronal calcium-sensor gene family. The expression of VSNL1 was regulated by the β-catenin/TCF7L2 complex via two TCF7L2-binding elements in intron 1. VSNL1 KD-induced apoptosis in VSNL1-positive CRC cells. Additionally, forced expression of wild-type VSNL1, but not a myristoylation, Ca²⁺ -binding, or dimerization-defective mutant, suppressed the apoptosis induced by camptothecin and doxorubicin in VSNL1-negative CRC cells.

Conclusion: Our findings suggest that VSNL1, a novel target gene of the Wnt/β-catenin signaling pathway, is associated with apoptosis resistance in CRC cells.