Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. 1757 25

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix (ECM), thus assisting invasion. Upregulation of MMPs, frequently reported in gliomas, is associated with aggressive behavior. WNK2 is a tumor suppressor gene expressed in normal brain, and silenced by promoter methylation in gliomas. Patients without WNK2 exhibited poor prognosis, and its downregulation was associated with increased glioma cell invasion. Here we showed that MMP2 expression and activity are increased in glioma cell lines that do not express WNK2. Also, WNK2 inhibited JNK, a process associated with decreasing levels of MMP2. Thus, WNK2 promoter methylation and silencing in gliomas is associated with increased JNK activation and MMP2 expression and activity, thus explaining in part tumor cell invasion potential.
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PMID:Silencing of the tumor suppressor gene WNK2 is associated with upregulation of MMP2 and JNK in gliomas. 2559 41