title: Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth.
abstract: Human cancer genome and epigenome projects aim to identify new cancer genes and targets for therapy that have been overlooked by conventional approaches. Here we integrated large-scale genomics and epigenomics of 31 human infiltrative gliomas and identified low-frequency deletion and highly recurrent epigenetic silencing of WNK2, encoding a putative serine/threonine kinase. Prior cancer genome sequencing projects also identified point mutations in WNK1-4, suggesting that WNK family genes may have a role in cancers. We observed consistent gene silencing in tumors with dense aberrant methylation across 1.3 kb of the CpG island but more variable expression when the 5'-most region remained unmethylated. This primary tumor data fit well with WNK2 promoter analysis, which showed strong promoter activity in the 5'-most region, equivalent to the simian virus 40 promoter, but no activity in the 3' region. WT WNK2 exhibited autophosphorylation and protein kinase activity that was enhanced in cells exposed to hypertonic conditions, similar to WNK1. WNK2 inhibited up to 78% of colony formation by glioma cells but in an unexpectedly kinase-independent manner. The WNK2 silencing by epigenetic mechanisms was significantly associated (P < 0.01) with a known genetic signature of chemosensitive oligodendroglial tumors, 1p and 19q deletion, in two small but independent tumor sets. Taken together, the epigenetic silencing, occasional deletion and point mutation, and functional assessment suggest that aberrations of WNK2 may contribute to unregulated tumor cell growth. Thus, our integrated genetic and epigenetic approach might be useful to identify genes that are widely relevant to cancer, even when genetic alterations of the locus are infrequent.
authors.affiliation: *Department of Neurological Surgery and the Comprehensive Cancer Center, University of California, San Francisco, CA 94143.
authors.forename: Chibo
authors.initials: C
authors.lastname: Hong
authors.forename: K Scott
authors.initials: KS
authors.lastname: Moorefield
authors.forename: Peter
authors.initials: P
authors.lastname: Jun
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Samir
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
mesh_terms: D024506:5' Flanking Region; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D020868:Gene Silencing; D052138:Genes, Neoplasm; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D010766:Phosphorylation; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D025521:Tumor Suppressor Proteins; C523482:WNK2 protein, human; D017346:Protein Serine-Threonine Kinases