The cancer/testis antigen HORMAD1 mediates epithelial-mesenchymal transition to promote tumor growth and metastasis by activating the Wnt/β-catenin signaling pathway in lung cancer.

The cancer/testis antigen HORMAD1 is a mechanical regulator that modulates DNA homologous recombination repair and mismatch repair in multiple cancers. However, the role and underlying regulatory mechanisms of HORMAD1 in lung cancer progression remain unknown. Here, we show that HORMAD1 is upregulated in lung adenocarcinoma tissues compared with adjacent normal tissues and that aberrant HORMAD1 expression predicts poor prognosis. We further demonstrate that HORMAD1 promotes the proliferation, migration and invasion of lung cancer cells both in vitro and in vivo by inducing epithelial-mesenchymal transition (EMT). Subsequent mechanistic investigations revealed that HORMAD1 activates the Wnt/β-catenin pathway by increasing the phosphorylation level of AKT at Ser473 and that of GSK-3β at Ser9 in lung cancer cells, which decreases the phosphorylation level of β-catenin at Ser33/37/Thr41, enhances the cytoplasmic and nuclear accumulation of β-catenin and its transcriptional activity, consequently promoting EMT and lung cancer growth and metastasis. Our results provide new insights into the functional role and regulatory mechanism of HORMAD1 in lung cancer progression and identify HORMAD1 as a promising prognostic biomarker and therapeutic target for lung cancer.