High VHL Expression Reverses Warburg Phenotype and Enhances Immunogenicity in Kidney Tumor Cells.

Abstract Clear cell renal cell carcinoma (ccRCC) is a frequently occurring renal cancer. Von Hippel-Lindau disease tumor suppressor (VHL), a known tumor suppressor, is frequently mutated in about 50% of patients with ccRCC. However, it is unclear whether VHL influences the progression of ccRCC tumors expressing wild-type VHL. In the present study, we found that higher expression of VHL was correlated with the better disease-free survival (DFS) in ccRCC patients using The Cancer Genome Atlas (TCGA) datasets. We revealed that VHL overexpression in ccRCC cells inhibited epithelial-mesenchymal transition (EMT), sterol regulatory element-binding protein 1 (SREBP1) regulated triglyceride synthesis, and cell proliferation. Proteomic analysis provided us a global view that VHL regulated four biological processes including metabolism, immune regulation, apoptosis, and cell movement. Importantly, we found that VHL overexpression led to upregulation of proteins associated with antigen processing and interferon-responsive proteins, rendering ccRCC cells with high VHL expression more sensitive to interferon treatment. We defined an interferon-responsive signature (IRS) with ten proteins, whose expression levels were positively correlated with DFS in ccRCC patients. Taken together, our results propose that the subset of ccRCC patients with high VHL expression benefit from immunotherapy.