Classic Protocadherin PCDH10 Functions as a Tumor Suppressive Scaffold Protein Antagonizing Oncogenic WNT/β-catenin...

Epigenetic mechanisms, including DNA methylation, frequently inactivate tumor suppressor genes (TSGs) in multiple tumorigeneses. This study investigated the molecular basis of the tumor-suppressive role of the classic protocadherin tumor suppressor PCDH10 in breast carcinogenesis. Frequent PCDH10 downregulation and promoter methylation was identified in breast cancer, correlating with poor prognosis and ER-negative status. Restoration of PCDH10 expression significantly suppressed tumorigenesis both in vitro and in vivo, by inhibiting epithelial-mesenchymal transition (EMT) and cancer stemness. RNA sequencing revealed PCDH10's role in Wnt/β-catenin signaling suppression. Mechanistically, PCDH10 enhanced GSK-3β phosphorylation at Try216, inhibited aberrant β-catenin activation and upregulated the expression of the tumor-suppressive nuclear envelope protein LMNA expression through direct binding. Concurrently, it also attenuated other oncogenic signaling via suppression of RhoA and Akt phosphorylation. Collectively, promoter CpG methylation-mediated silencing of PCDH10 promotes breast cancer progression. PCDH10 restoration antagonizes tumorigenesis by dual blockade of Wnt/β-catenin and Akt signaling pathways through interactions with GSK-3β, β-catenin, and LMNA, as a scaffold protein. Our findings reveal a novel PCDH10-dependent tumor-suppressive axis and highlight its potential as a therapeutic target and biomarker in breast cancer.