HPCAL1 promotes colorectal cancer progression via TCF7/p65-mediated Wnt ligand upregulation and Wnt/β-catenin pathway activation.

Abnormal Wnt/β-catenin pathway activation drives colorectal cancer (CRC) tumorigenesis, yet effective targeted therapies remain elusive. Given HPCAL1's established dual tumor-suppressive and oncogenic roles in other cancers, this study investigates its function in CRC to assess the therapeutic potential. Bioinformatic analyses of publicly available CRC datasets supported by in-house cohort studies linked high HPCAL1 expression in primary CRC tissues with clinicopathological factors associated with metastasis and worsened patient outcomes. Knockdown and overexpression studies in cell lines showed that HPCAL1 positively contributes to CRC cell motility and invasion, as well as proliferation in vitro and in vivo in xenografts. RNA sequencing linked HPCAL1 expression with the Wnt/β-catenin pathway, demonstrating positive correlations with Wnt ligands in CRC models and clinical samples. Biochemical approaches showed HPCAL1 augmented the activation and nuclear localization of β-catenin. Moreover, HPCAL1 formed distinct complexes with β-catenin in tandem with the TCF7 or p65 transcription factors, in turn, differentially transactivating Wnt6, Wnt7A, and Wnt11 ligands. Notably, the anticancer activity of desloratadine against CRC cells, a pharmacological inhibitor of HPCAL1, functioned by curtailing Wnt6, Wnt7A, and Wnt11 expression and suppressing Wnt/β-catenin signaling. Collectively, these findings indicate that HPCAL1 is a significant contributor to the clinical aggressiveness of CRC with oncogenic effects intrinsically linked with sustaining canonical Wnt pathway activation. Furthermore, drug targeting experiments provide proof-of-principle evidence for promoting HPCAL1 as a therapeutic target for countering activated Wnt/β-catenin signaling in colorectal cancer.