NADPH Oxidase NOX4 Supports Renal Tumorigenesis by Promoting the Expression and Nuclear Accumulation of HIF2α

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 13; pp. 3501 - 3511
• Main Authors: GREGG, Jennifer L, TURNER, Robert M, GUIMIN CHANG, JOSHI, Disha, YE ZHAN, LI CHEN, MARANCHIE, Jodi K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2014
• Subjects: Animals; Antineoplastic agents; Basic Helix-Loop-Helix Transcription Factors - biosynthesis; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Carcinoma, Renal Cell - pathology; Catalase - biosynthesis; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Cyclic N-Oxides - pharmacology; Female; Gene Expression Regulation, Neoplastic; Humans; Kidney - pathology; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Medical sciences; Mice; Mice, SCID; NADPH Oxidase 4; NADPH Oxidases - genetics; Neoplasm Transplantation; Pharmacology. Drug treatments; Protein Synthesis Inhibitors - pharmacology; RNA Interference; Spin Labels; Superoxide Dismutase - biosynthesis; Superoxides - metabolism; Tumors; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; Urinary system; Enzyme; Tumorigenicity; Oxidoreductases; Gene expression; Carcinogenesis; Kidney; NAD(P)H oxidase
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-2979

Most sporadically occurring renal tumors include a functional loss of the tumor suppressor von Hippel Lindau (VHL). Development of VHL-deficient renal cell carcinoma (RCC) relies upon activation of the hypoxia-inducible factor-2α (HIF2α), a master transcriptional regulator of genes that drive diverse processes, including angiogenesis, proliferation, and anaerobic metabolism. In determining the critical functions for HIF2α expression in RCC cells, the NADPH oxidase NOX4 has been identified, but the pathogenic contributions of NOX4 to RCC have not been evaluated directly. Here, we report that NOX4 silencing in VHL-deficient RCC cells abrogates cell branching, invasion, colony formation, and growth in a murine xenograft model RCC. These alterations were phenocopied by treatment of the superoxide scavenger, TEMPOL, or by overexpression of manganese superoxide dismutase or catalase. Notably, NOX4 silencing or superoxide scavenging was sufficient to block nuclear accumulation of HIF2α in RCC cells. Our results offer direct evidence that NOX4 is critical for renal tumorigenesis and they show how NOX4 suppression and VHL re-expression in VHL-deficient RCC cells are genetically synonymous, supporting development of therapeutic regimens aimed at NOX4 blockade.