Identification of novel VHL regulated genes by transcriptomic analysis of RCC10 renal carcinoma cells Sarah K. Harten a , Miguel A. Esteban b , Patrick H. Maxwell a, * a Division of Medicine, Rayne Institute, University College London, University Street, London WC1E 6JJ, UK b South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, PR China Introduction Renal cell carcinomas account for approximately 2% of all adult cancers and cause approximately 100,000 deaths per year worldwide (Parkin et al., 2005). The majority of these tumours (w80%) are classified as ‘clear cell’ tumours, based on their microscopic appearance (Motzer et al., 1996). Germline mutations of the von Hippel–Lindau (VHL) tumour suppressor gene gives rise to the inherited multi- cancer syndrome VHL disease. Patients are predisposed to a variety of tumours including clear cell renal cell carcinomas (CCRCCs), pheochromocytomas, hemangioblastomas of the retina and central nervous system and benign cysts affecting a variety of organs (Kondo and Kaelin, 2001). Notably, biallelic VHL inactivation also underlies the majority of sporadic CCRCCs, providing an excellent example of Knud- son’s two hit model of tumour suppressor gene inactivation (Nickerson et al., 2008). Identification of VHL’s role in the renal epithelium has already offered valuable insight into the biology of CCRCC. Typically, CCRCCs present late in the course of the disease, with 30% of patients presenting with metastatic disease (Motzer et al., 1996). Clinically treatment of renal cancer remains challenging. It is hoped that further insight gained from determining VHL’s role will lead to new therapeutic approaches. The best established biochemical function of VHL protein (pVHL) is regulation of the hypoxia inducible transcription factor HIF (Wang and Semenza, 1993; Maxwell et al., 1999). When oxygen is present specific proline residues within the HIF-a subunits are hydroxylated by a group of iron and 2-oxoglutarate dependent enzymes known as the prolyl hydroxylase domain (PHD) enzymes (alter- native names are EGLN and HIF-PH) (Epstein et al., 2001; Hewitson et al., 2003). pVHL acts as the recognition subunit of a multi-protein complex with ubiquitin E3 ligase activity, which targets the hydroxylated HIF-a subunits for destruction (Maxwell et al., 1999; Cockman et al., 2000; Jaakkola et al., 2001). During hypoxia, or when VHL is inactivated, HIF-a subunits accumulate. This allows the formation of a HIF complex with HIF-1b. HIF then binds to hypoxia response elements (HREs) to modulate the expression of a large number of target genes involved in diverse pathways including; * Corresponding author. E-mail address: p.maxwell@ucl.ac.uk (P.H. Maxwell). Contents lists available at ScienceDirect Advances in Enzyme Regulation journal homepage: www.elsevier.com/locate/ advenzreg 0065-2571/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.advenzreg.2008.12.005 Advances in Enzyme Regulation 49 (2009) 43–52