Putative tumour suppressor gene necdin is hypermethylated and mutated in human cancer

Expression of telomerase is detected in the majority of human tumours and allows cells to avoid replicative senescence by maintaining telomere length. Telomere-independent effects are also described (Smith et al, 2003). Expression array analysis identified genes that are consistently altered in telomerase-immortalised NHUC (TERT-NHUC; Chapman et al, 2006) compared with isogenic mortal counterparts (Chapman et al, 2008). During these studies we identified Necdin (NDN) as a candidate tumour suppressor gene. NDN maps to 15q11, a maternally imprinted region implicated in Prader–Willi syndrome (PWS). Necdin is a multifunctional protein. Due to its association with PWS, interest has focused on its role in neuronal development and differentiation (Kuwajima et al, 2006). However, it also has functions that could be of importance in suppression of tumorigenesis (Chapman and Knowles, 2009). In vitro studies demonstrate the role of NDN in suppression of colony formation and haematopoietic stem cell quiescence (Liu et al, 2009). Anti-angiogenic effects have also been described (Moon et al, 2005). For the first time, we have examined expression of NDN protein in a range of normal human tissues and tumour cell lines. Novel mutations in NDN were identified. Methylation of NDN has been examined in tumour cell lines and primary urothelial carcinoma (UC). Annually, in the UK, more than 10 000 people are diagnosed with UC. Ninety per cent of cases are transitional cell carcinoma, derived from the cells lining the bladder, the remainder of cases are squamous cell carcinoma or adenocarcinoma. Rarely, sarcoma or small-cell carcinoma are observed. Integration of expression and hypermethylation data has allowed identification of key CpG sites involved in transcriptional silencing. Oncomine expression microarray data were examined to determine the expression of NDN transcript in multiple tumour types compared with normal tissue. The functional significance of NDN expression was examined in vitro using retroviral-mediated transduction. We present the first evidence to support our hypothesis that NDN is a potential tumour suppressor gene with a role in multiple tumour types (Chapman and Knowles, 2009).