KDM6A deficiency promotes tumor progression and resistance to cabozantinib treatment in clear cell renal cell carcinoma.

Lysine (K)-specific demethylase (KDM) 6A, a histone modifier with inhibitory roles in many types of cancers, is frequently mutated in clear cell renal cell carcinoma (ccRCC). Here, we investigated the role of KDM6A in ccRCC progression, including its effect on resistance to tyrosine kinase inhibitors (TKIs). The clinical impact of KDM6A expression was examined by immunohistochemical analysis of nephrectomized tissues from patients with ccRCC. Upon generation of KDM6A-deficient RCC cells by CRISPR/Cas9-mediated gene editing, in vitro cancer cell property analysis, RNA sequencing, and in vivo murine xenograft model examination were performed. The relationship between KDM6A expression and efficacy of TKIs was analyzed using data from public databases and in vitro pharmacological assessments. Patients with KDM6A-low ccRCC had poor prognoses. Promoted invasion, migration, cancer stemness, epithelial-mesenchymal transition (EMT), and in vivo tumor progression were observed in KDM6A-deficient RCC cells. A reanalysis of previous clinical trial data revealed lower efficacy of sunitinib in patients with KDM6A-low ccRCC. Consistently, KDM6A-deficient cells showed resistance to cabozantinib and decreased expression of target molecules of TKIs. KDM6A deficiency contributes to ccRCC progression and TKI resistance, suggesting that targeting KDM6A-related pathways may offer new therapeutic strategies for patients with KDM6A-deficient ccRCC.