Long-range Enhancers on 8q24 Regulate C-Myc

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Feb 6

PMID 20133699

Citations 139

Authors

Jose Sotelo

Dominic Esposito

Maria Ana Duhagon

Kelley Banfield

Jennifer Mehalko

Hongling Liao

Robert M Stephens

Timothy J R Harris

David J Munroe

Xiaolin Wu

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Data-driven projections of candidate enhancer-activating SNPs in immune regulation.

Hoffmann M, Vaz T, Chhatrala S, Hennighausen L BMC Genomics. 2025; 26(1):197.

PMID: 40011812 PMC: 11863423. DOI: 10.1186/s12864-025-11374-7.

Multiple allelic configurations govern long-range Shh enhancer-promoter communication in the embryonic forebrain.

Harke J, Lee J, Nguyen S, Arab A, Rakowiecki S, Hugelier S Mol Cell. 2024; 84(24):4698-4710.e6.

PMID: 39579767 PMC: 11663103. DOI: 10.1016/j.molcel.2024.10.042.

Selective Enhancer Gain-of-Function Deregulates MYC Expression in Multiple Myeloma.

Rahmat M, Clement K, Alberge J, Sklavenitis-Pistofidis R, Kodgule R, Fulco C Cancer Res. 2024; 84(24):4173-4183.

PMID: 39312195 PMC: 11649448. DOI: 10.1158/0008-5472.CAN-24-1440.

Extrachromosomal circular DNA promotes prostate cancer progression through the FAM84B/CDKN1B/MYC/WWP1 axis.

Jin W, Xu Z, Song Y, Chen F Cell Mol Biol Lett. 2024; 29(1):103.

PMID: 38997648 PMC: 11245840. DOI: 10.1186/s11658-024-00616-3.

Regulation of Myc transcription by an enhancer cluster dedicated to pluripotency and early embryonic expression.

Li-Bao L, Diaz-Diaz C, Raiola M, Sierra R, Temino S, Moya F Nat Commun. 2024; 15(1):3931.

PMID: 38729993 PMC: 11087473. DOI: 10.1038/s41467-024-48258-5.

References

Haiman C, Le Marchand L, Yamamato J, Stram D, Sheng X, Kolonel L . A common genetic risk factor for colorectal and prostate cancer. Nat Genet. 2007; 39(8):954-6. PMC: 2391283. DOI: 10.1038/ng2098. View

Zanke B, Greenwood C, Rangrej J, Kustra R, Tenesa A, Farrington S . Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet. 2007; 39(8):989-94. DOI: 10.1038/ng2089. View

Korsmeyer S . Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. Annu Rev Immunol. 1992; 10:785-807. DOI: 10.1146/annurev.iy.10.040192.004033. View

Visakorpi T, Kallioniemi A, Syvanen A, Hyytinen E, Karhu R, Tammela T . Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. Cancer Res. 1995; 55(2):342-7. View

Murphy D, Junttila M, Pouyet L, Karnezis A, Shchors K, Bui D . Distinct thresholds govern Myc's biological output in vivo. Cancer Cell. 2008; 14(6):447-57. PMC: 2723751. DOI: 10.1016/j.ccr.2008.10.018. View

Nobrega M, Ovcharenko I, Afzal V, Rubin E . Scanning human gene deserts for long-range enhancers. Science. 2003; 302(5644):413. DOI: 10.1126/science.1088328. View

Witte J . Multiple prostate cancer risk variants on 8q24. Nat Genet. 2007; 39(5):579-80. DOI: 10.1038/ng0507-579. View

Heintzman N, Hon G, Hawkins R, Kheradpour P, Stark A, Harp L . Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature. 2009; 459(7243):108-12. PMC: 2910248. DOI: 10.1038/nature07829. View

Dekker J, Rippe K, Dekker M, Kleckner N . Capturing chromosome conformation. Science. 2002; 295(5558):1306-11. DOI: 10.1126/science.1067799. View

10.

Liu J, Levens D . Making myc. Curr Top Microbiol Immunol. 2006; 302:1-32. DOI: 10.1007/3-540-32952-8_1. View

11.

Haiman C, Patterson N, Freedman M, Myers S, Pike M, Waliszewska A . Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007; 39(5):638-44. PMC: 2638766. DOI: 10.1038/ng2015. View

12.

Stewart C, Schuetze S, Vanek M, Wagner E . Expression of retroviral vectors in transgenic mice obtained by embryo infection. EMBO J. 1987; 6(2):383-8. PMC: 553407. DOI: 10.1002/j.1460-2075.1987.tb04766.x. View

13.

Lowe S, Cepero E, Evan G . Intrinsic tumour suppression. Nature. 2004; 432(7015):307-15. DOI: 10.1038/nature03098. View

14.

Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Kemp Z, Spain S . A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet. 2007; 39(8):984-8. DOI: 10.1038/ng2085. View

15.

Ribeiro F, Jeronimo C, Henrique R, Fonseca D, Oliveira J, Lothe R . 8q gain is an independent predictor of poor survival in diagnostic needle biopsies from prostate cancer suspects. Clin Cancer Res. 2006; 12(13):3961-70. DOI: 10.1158/1078-0432.CCR-05-1977. View

16.

Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E . Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell. 2006; 124(1):47-59. DOI: 10.1016/j.cell.2005.10.042. View

17.

Wierstra I, Alves J . The c-myc promoter: still MysterY and challenge. Adv Cancer Res. 2007; 99:113-333. DOI: 10.1016/S0065-230X(07)99004-1. View

18.

Gudmundsson J, Sulem P, Manolescu A, Amundadottir L, Gudbjartsson D, Helgason A . Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet. 2007; 39(5):631-7. DOI: 10.1038/ng1999. View

19.

Yeager M, Orr N, Hayes R, Jacobs K, Kraft P, Wacholder S . Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007; 39(5):645-9. DOI: 10.1038/ng2022. View

20.

Easton D, Pooley K, Dunning A, Pharoah P, Thompson D, Ballinger D . Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007; 447(7148):1087-93. PMC: 2714974. DOI: 10.1038/nature05887. View