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Molecular and Cellular Biology, January 2003, p. 206-215, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.206-215.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Critical Role of Histone Methylation in Tumor Suppressor Gene Silencing in Colorectal Cancer

Yutaka Kondo, LanLan Shen, and Jean-Pierre J. Issa*

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Received 28 August 2002/ Accepted 1 October 2002

The mechanism of DNA hypermethylation-associated tumor suppressor gene silencing in cancer remains incompletely understood. Here, we show by chromatin immunoprecipitation that for three genes (P16, MLH1, and the O6-methylguanine-DNA methyltransferase gene, MGMT), histone H3 Lys-9 methylation directly correlates and histone H3 Lys-9 acetylation inversely correlates with DNA methylation in three neoplastic cell lines. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) resulted in moderately increased Lys-9 acetylation at silenced loci with no effect on Lys-9 methylation and minimal effects on gene expression. By contrast, treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza-dC) rapidly reduced Lys-9 methylation at silenced loci and resulted in reactivation for all three genes. Combined treatment with 5Aza-dC and TSA was synergistic in reactivating gene expression through simultaneous effects on Lys-9 methylation and acetylation, which resulted in a robust increase in the ratio of Lys-9 acetylated and methylated histones at loci showing dense DNA methylation. By contrast to Lys-9, histone H3 Lys-4 methylation inversely correlated with promoter DNA methylation, was not affected by TSA, and was increased moderately at silenced loci by 5Aza-dC. Our results suggest that reduced H3 Lys-4 methylation and increased H3 Lys-9 methylation play a critical role in the maintenance of promoter DNA methylation-associated gene silencing in colorectal cancer.

* Corresponding author. Mailing address: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Box 428, 1515 Holcombe, Houston, TX 77030. Phone: (713) 745-2260. Fax: (713) 794-4297. E-mail: jpissa{at}mdanderson.org.

Molecular and Cellular Biology, January 2003, p. 206-215, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.206-215.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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