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15-Lipoxygenase-1 transcriptional silencing by DNA methyltransferase-1 independently of DNA methylation

Xiangsheng Zuo^*, Lanlan Shen, Jean-Pierre Issa, Ofir Moy^*, Jeffrey S. Morris, Scott M. Lippman^*, and Imad Shureiqi^*,||,1

^* Department of Clinical Cancer Prevention,

Department of Leukemia,

Department of Biostatistics and Applied Mathematics,

Department of Thoracic/Head and Neck Medical Oncology, and

^|| Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

¹Correspondence: Department of Clinical Cancer Prevention, Unit 1360, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009, USA. E-mail: ishureiqi{at}mdanderson.org

Methylation of promoter DNA contributes to transcriptional silencing of various tumor-suppressor genes in cancer. Transcriptional silencing of 15-lipoxygenase-1 (15-LOX-1) promotes tumorigenesis. Methylation of 15-LOX-1 promoter DNA occurs in some cancers, but its mechanistic role in 15-LOX-1 transcriptional silencing is unclear. We examined the mechanistic role of 15-LOX-1 promoter DNA methylation in 15-LOX-1 transcriptional regulation in human colorectal cancers. 15-LOX-1 promoter methylation occurred in colorectal cancer cells in vitro, in 36% of tumor tissue samples of colorectal cancer patients, and in virtually no normal colonic mucosa samples of 50 human subjects with no history of colorectal cancer or polyps. 15-LOX-1 promoter DNA methylation levels, however, did not correlate with 15-LOX-1 expression levels (Spearman’s r=0.21; P=0.38). We employed siRNA knockdown and genetic disruption models of DNA methyltransferases (DNMTs) to study the effects of this methylation on 15-LOX-1 expression in colon cancer cells. 15-LOX-1 promoter demethylation was insufficient to reestablish 15-LOX-1 expression. 15-LOX-1 transcription was activated by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) only after DNMT-1 dissociation from the 15-LOX-1 promoter and without altering 15-LOX-1 promoter DNA methylation. DNMT-1 protein hypomorphism impaired DNMT-1 recruitment to the 15-LOX-1 promoter, which allowed 15-LOX-1 transcription activation by SAHA. DNMT-1 has a direct suppressive role in 15-LOX-1 transcriptional silencing that is independent of 15-LOX-1 promoter DNA methylation.—Zuo, X., Shen, L., Issa, J. P., Moy, O., Morris, J. S., Lippman, S. M., Shureiqi, I. 15-Lipoxygenase-1 transcriptional silencing by DNA methyltransferase-1 independently of DNA methylation.

Key Words: colon cancer • transcriptional regulation • histone deacetylase inhibitor • DNMT-1 hypomorph protein

This article has been cited by other articles:

				X. Zuo, J. S. Morris, and I. Shureiqi Chromatin Modification Requirements for 15-Lipoxygenase-1 Transcriptional Reactivation in Colon Cancer Cells J. Biol. Chem., November 14, 2008; 283(46): 31341 - 31347. [Abstract] [Full Text] [PDF]