Calcitriol alleviates ARID2-deficient gastric cancer metastasis via inhibition of the Wnt/β-catenin signaling pathway.

INTRODUCTION: Somatic mutations of the chromatin remodeling gene ARID2 occur at a higher frequency in gastric cancer (GC) and correlate with poor prognosis. However, the mechanisms by which ARID2 impacts GC progression remain largely unknown. METHODS: Functional and mechanistic studies were conducted to investigate how ARID2 deficiency promotes GC metastasis via activation of the Wnt pathway. Integrative RNA-seq and CUT&Tag identified vitamin D receptor (VDR) as a key transcription factor in ARID2-knockdown GC cells. CUT&RUN qPCR and luciferase reporter assays were used to detect ARID2 occupancy at the VDR promoter and the effects of ARID2 on VDR promoter activity, respectively. The in vivo findings were further validated in peritoneal metastasis models. RESULTS: Our study demonstrated that ARID2 deficiency was associated with shorter progression-free survival in GC patients with lymph node metastasis. Mechanistically, ARID2 was enriched at the VDR promoter and promoted VDR transcription. Consequently, ARID2 knockdown led to VDR downregulation, which abolished VDR-mediated suppression of the Wnt signaling, resulting in the nuclear accumulation of β-catenin and GC metastasis. Strikingly, restoration of VDR signaling via genetic overexpression or administration of the VDR agonist 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol) specifically blocked β-catenin nuclear localization, thereby profoundly suppressing the metastatic progression of ARID2-deficient GC in vitro and in vivo. CONCLUSIONS: This study identifies the VDR-mediated Wnt/β-catenin signaling axis as a crucial mechanism through which ARID2 knockdown promotes GC cell metastasis. More significantly, VDR activation by calcitriol effectively reverses oncogenic changes.