Long-range enhancers on 8q24 regulate c-Myc

Recent genomewide association studies have found multiple genetic variants on chromosome 8q24 that are significantly associated with an increased susceptibility to prostate, colorectal, and breast cancer. These risk loci are located in a ”gene desert,” a few hundred kilobases telomeric to the Myc gene. To date, the biological mechanism(s) underlying these associations remain unclear. It has been speculated that these 8q24 genetic variant(s) might affect Myc expression by altering its regulation or amplification status. Here, we show that multiple enhancer elements are present within this region and that they can regulate transcription of Myc. We also demonstrate that one such enhancer element physically interacts with the Myc promoter via transcription factor Tcf-4 binding and acts in an allele specific manner to regulate Myc expression.

[1]  C. Babinet,et al.  The cis-acting elements known to regulate c-myc expression ex vivo are not sufficient for correct transcription in vivo. , 1994, Oncogene.

[2]  A. Gylfason,et al.  A common variant associated with prostate cancer in European and African populations , 2006, Nature Genetics.

[3]  P. Fearnhead,et al.  Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 , 2007, Nature Genetics.

[4]  Wouter de Laat,et al.  Quantitative analysis of chromosome conformation capture assays (3C-qPCR) , 2007, Nature Protocols.

[5]  Lester L. Peters,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2007, Nature.

[6]  A. Le Cam,et al.  Characterization of an enhancer element in the proximal promoter of the mouse glucagon receptor gene. , 2001, Biochimica et biophysica acta.

[7]  K. Kinzler,et al.  Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma , 1997, Science.

[8]  G. Evan,et al.  Distinct thresholds govern Myc's biological output in vivo. , 2008, Cancer cell.

[9]  L. Shulman,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2008 .

[10]  E. Ukkonen,et al.  Genome-wide Prediction of Mammalian Enhancers Based on Analysis of Transcription-Factor Binding Affinity , 2006, Cell.

[11]  Steven Gallinger,et al.  Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24 , 2007, Nature Genetics.

[12]  Thomas Ried,et al.  Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors , 1996, Genes, chromosomes & cancer.

[13]  E. Wagner,et al.  Expression of retroviral vectors in transgenic mice obtained by embryo infection. , 1987, The EMBO journal.

[14]  P. Carroll,et al.  Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. , 1996, Cancer research.

[15]  A. Whittemore,et al.  Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men , 2006, Proceedings of the National Academy of Sciences.

[16]  N. Carter,et al.  Array Comparative Genomic Hybridization Analysis of Colorectal Cancer Cell Lines and Primary Carcinomas , 2004, Cancer Research.

[17]  J. Dekker,et al.  Capturing Chromosome Conformation , 2002, Science.

[18]  T. Visakorpi,et al.  Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. , 1995, Cancer research.

[19]  S. Korsmeyer,et al.  Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. , 1992, Annual review of immunology.

[20]  M. Nóbrega,et al.  Scanning Human Gene Deserts for Long-Range Enhancers , 2003, Science.

[21]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[22]  Oliver Sieber,et al.  A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21 , 2007, Nature Genetics.

[23]  R. Lothe,et al.  8q Gain Is an Independent Predictor of Poor Survival in Diagnostic Needle Biopsies from Prostate Cancer Suspects , 2006, Clinical Cancer Research.

[24]  A. Whittemore,et al.  Multiple regions within 8q24 independently affect risk for prostate cancer , 2007, Nature Genetics.

[25]  E. Wagner,et al.  Transfer of genes into embryonal carcinoma cells by retrovirus infection: efficient expression from an internal promoter. , 1985, The EMBO journal.

[26]  Hans Clevers,et al.  Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells , 2008, Molecular and Cellular Biology.

[27]  Colin E Bishop,et al.  Long-range activation of Sox9 in Odd Sex (Ods) mice. , 2004, Human molecular genetics.

[28]  David Reich,et al.  A common genetic risk factor for colorectal and prostate cancer , 2007, Nature Genetics.

[29]  I. Wierstra,et al.  The c-myc promoter: still MysterY and challenge. , 2008, Advances in cancer research.

[30]  Nathaniel D. Heintzman,et al.  Histone modifications at human enhancers reflect global cell-type-specific gene expression , 2009, Nature.

[31]  J. Liu,et al.  Making myc. , 2006, Current topics in microbiology and immunology.

[32]  S. Lowe,et al.  Intrinsic tumour suppression , 2004, Nature.

[33]  J. Witte.  Multiple prostate cancer risk variants on 8q24 , 2007, Nature Genetics.

[34]  D. Gudbjartsson,et al.  Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24 , 2007, Nature Genetics.