Prognostic significance and function of the vacuolar H+-ATPase subunit V1E1 in esophageal squamous cell carcinoma

// Sung Wook Son 1, * , Seok-Hyung Kim 2, 3, * , Eun-Yi Moon 4, * , Dong-Hoon Kim 5 , Suhkneung Pyo 6 , Sung Hee Um 1, 3 1 Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Gyeonggi-do, 16419, Korea 2 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea 3 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, 06351, Korea 4 Department of Bioscience and Biotechnology, Sejong University, Seoul, 05006, Korea 5 Department of Pharmacology, Korea University College of Medicine, Seoul, 02841, Korea 6 Division of Immunopharmacology, School of Pharmacy, Sungkyunkwan University, Gyeonggi-do, 16419, Korea * These authors have contributed equally to this work Correspondence to: Sung Hee Um, email: shum@skku.edu Keywords: V-ATPase subunit V1E1, esophageal squamous cell carcinoma (ESCC), cell motility, aerobic glycolysis, prognosis Received: April 05, 2016      Accepted: June 13, 2016      Published: June 30, 2016 ABSTRACT Vacuolar H +- ATPase (V-ATPase), a hetero-multimeric ATP-driven proton pump has recently emerged as a critical regulator of mTOR-induced amino acid sensing for cell growth. Although dysregulated activity of cell growth regulators is often associated with cancer, the prognostic significance and metabolic roles of V-ATPase in esophageal cancer progression remain unclear. Here, we show that high levels of V-ATPase subunit V1E1 (V-ATPase V1E1) were significantly associated with shortened disease-free survival in patients with esophageal squamous cell carcinoma (ESCC). Multivariate analysis identified the V-ATPase V1E1 as an independent adverse prognostic factor (hazard ratio;1.748, P = 0.018). In addition, depletion of V-ATPase V1E1 resulted in reduced cell motility, decreased glucose uptake, diminished levels of lactate, and decreased ATP production, as well as inhibition of glycolytic enzyme expression in TE8 esophageal cancer cells. Consistent with these results, the Cancer Genome Atlas (TCGA) data and Gene Set Enrichment Analysis (GSEA) showed a high frequency of copy number alterations of the V-ATPase V1E1 gene, and identified a correlation between levels of V-ATPase V1E1 mRNA and Pyruvate Kinase M2 (PKM2) in ESCC. High expression levels of both V-ATPase V1E1 and phosphorylated PKM2 (p-PKM2), a key player in cancer metabolism, were associated with poorer prognosis in ESCC. Collectively, our findings suggest that expression of the V-ATPase V1E1 has prognostic significance in ESCC, and is closely linked to migration, invasion, and aerobic glycolysis in esophageal cancer cells.