Dr Karim Malik
Reader in Epigenetics
School of Cellular and Molecular Medicine,
University of Bristol, Medical Sciences Building,
Bristol, BS8 1TD
phone: +44 (0)117 33 12078 (internal 12078)
group: Cancer Epigenetics Lab
Figure 1. Analysis of the Wilms' tumour epigenome. (A) shows a region of long-range epigenetic silencing (LRES) on human chromosome 5q31 identified by human genome promoter arrays. (B) Clustered paralogous protocadherin genes at chromosome 5q31 are hypermethylated in Wilms' tumour.
As well as genetic lesions, cancer cells also acquire defects in regulating levels of gene expression, which can lead to their enhanced survival and inappropriate growth. Epigenetics is a key mechanism for regulating gene expression levels, and is dependent on modification of DNA and chromatin by reversible enzymatic modifications such as methylation.
My group are using genome-wide epigenetic analysis of cancer cells to identify novel tumour suppressor genes and oncogenes that may, when deregulated, contribute to tumorigenesis. The functions of proteins encoded by deregulated genes, such as the protocadherins shown in figure 1, are also assessed as this may lead to new therapeutic strategies for cancer in the future. In addition, we are also interested in the developmental functions of such genes within the kidney.
We are also investigating novel drugs that may be utilised in the treatment of neuroblastoma, a paediatric cancer with poor prognosis. By modulating the epigenetic machinery, such drugs may be effective in driving differentiation and/or cell-death of cancer cells (see figure 2).
Figure 2. Differentiation of neuroblastoma cells induced by drugs modulating the epigenetic machinery. The treated cells (right panel) show neurites indicative of differentiation.
- Dr Anthony Dallosso (Cancer Research UK)
- Dr Marianna Szemes (Kidney Research UK)
- Phillipa Bird (EPSRC PhD student)
- Mr. Tom Curry (University technician)
- Szemes, M., Dallosso, A.R., Melegh, Z., Curry, T., Li, Y., Rivers, C., Uney, J., Mägdefrau, A., Schwiderski, K., Park, J., Brown, K.W., Shandilya, J., Roberts, S.G.E. and Malik, K. (2012) Control of epigenetic states by WT1 via regulation of de novo DNA methyltransferase 3A. Human Molecular Genetics (in press).
- Brown, K.W., Charles, A., Dallosso, A.R., White, G., Charlet, J., Standen, G.R. and Malik, K. (2012) Characterization of 17.94, a novel anaplastic Wilms' tumor cell line. Cancer Genetics (in press).
- Dallosso, A.R., Øster, B., Greenhough, A., Thorsen, K., Curry, T.J., Owen, C., Hancock, A.L., Szemes, M., Paraskeva, C., Frank, M., Andersen, C.L. and Malik, K. (2012) Long-range epigenetic silencing of chromosome 5q31 protocadherins is involved in early and late stages of colorectal tumorigenesis through modulation of oncogenic pathways. Oncogene Advanced online publication 16 Jan 2012.
- Kim, M.S., Yoon, S.K., Bollig, F., Kitagaki, J., Hur, W., Whye, N.J., Wu, Y.P., Rivera, M.N., Park, J.Y., Kim, H.S., Malik, K., Bell, D.W., Englert, C., Perantoni, A.O. and Lee, S.B. (2010). A novel Wilms Tumor 1 (WT1) target gene negatively regulates the WNT signaling pathway. J. Biol. Chem. 285(19), 14585-14593.
- Dallosso, A.R., Hancock, A.L., Szemes, A., Moorwood, K., Chilukamarri, L., Tsai, H-H., Sarkar, A., Barasch, J., Vuononvirta, R., Jones, C., Pritchard-Jones, K.m Royer-Pokora, B., Lee, S.B., Owen, C., Malik, S., Feng, Y., Frank, M., Ward, A., Brown, K.W. and Malik, K. (2009) Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms' Tumor. PLoS Genetics, 5(11), e1000745 [Available online].
- Brown, K.W., Power, F., Moore, B., Charles, A.K., and Malik, K.T.A. (2008) Frequency and timing of loss of imprinting at 11p13 and 11p15 in Wilms' Tumor development. Mol. Cancer Res. 6, 1114-1123.
- Chilukamarri, L.N.M., Hancock, A.L., Malik, S., Zabkiewicz, J., Baker, J.A., Greenhough, A., Dallosso, A.R., Hui-Ming Huang, T., Royer-Pokora, B., Brown, K.W., and Malik, K. (2007) Hypomethylation and aberrant expression of the Glioma pathogenesis-related 1 gene in Wilms' tumours, Neoplasia 9(11), 970-978.
- Dallosso, A.R., Hancock, A.L., Malik, S., Salpekar, A., King-Underwood, L., Pritchard-Jones, K., Peters, J., Moorwood, K., Ward, A., Malik, K. and Brown, K.W. (2007) Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer. RNA 13(12), 2287-2299.
- Kim, H-S., Kim, M.S., Hancock, A.L., Harper, J.C.P., Park, J.Y., Poy, G., Perantoni, A.O., Cam, M., Malik, K. and Lee, S.B.(2007) Identification of novel Wilms' Tumor suppressor gene target genes implicated in kidney development. Journal of Biological Chemistry 282(22), 16278-16287.
- Hancock, A.L., Brown, K.W., Moorwood, K., Moon, H., Holmgren, C., Mardikar, S.H., Dallosso, A.R., Klenova, E., Loukinov, D., Ohlsson, R., Lobanenkov, V.V. and Malik, K. (2007) A CTCF-binding silencer regulates the imprinted genes AWT1 and WT1-AS, and exhibits sequential epigenetic defects during Wilms' tumourigenesis. Human Molecular Genetics 16(3), 343-354.
- Dallosso, A.R., Hancock, A.L., Brown, K.W., Williams, A.C., Jackson, S. and Malik, K. (2004) Genomic Imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours. Human Molecular Genetics 13, 405-415.
- Malik, K., Salpekar, A., Hancock, A., Moorwood, K., Jackson, S., Charles, A. and Brown, K.W. (2000) Identification of differential methylation of the WT1 antisense regulatory region and relaxation of imprinting in Wilms' tumor. Cancer Research, 60, 2356-2360.
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