Inhibition of de novo Methyltransferase 3B is a Potential Therapy for Hepatocellular Carcinoma

Hong Fan, Jian Cheng, Zhu Jiang Zhao

Abstract


Background: Aberrant epigenetic patterns, including inactivation of tumor suppressor genes due to DNA methylation, have been described in many human cancers. Epigenetic therapeutic is a new and rapidly developing area of tumor treatment because DNA methyltransferase (DNMT) inhibitors can reverse its changes. We attempted to identify potential approach for epigenetic therapy of hepatocellular carcinoma.
Methods: We knocked down the expression of DNMT 1 or DNMT 3B by siRNA, and inhibited DNA methyltranferases by 5-Aza-2-deoxycytidine. We used high-density oligonucleotide gene expression microarrays to examine the induced genes in human hepatocellular carcinoma cell line SMMC-7721 after suppressing DNA methyltranferases. The 5 ends of up-regulated genes were analyzed by BLAST database to determine whether they have promoter CpG islands, and then the identical induced genes were compared among different inhibition of DNA methyltranferases.
Results: Our results show that 9 genes were found to be over expressed by more than two-fold induced by DNMT1 siRNA and 5-Aza-CdR, and 30 genes were found to be over expressed by more than two-fold induced by DNMT3B siRNA and 5-Aza-CdR in SMMC-7721. Among them, 76.6% up-regulated genes conjectural contained 5 CpG islands. The DNMT3B siRNA could induce more genes identical to demethylation agent in SMMC-7721.
Conclusions: DNMT3B might be a new potential target for therapy of hepatocellular carcinoma.

doi:10.4021/gr2008.10.1240


Keywords


Epigenetic, therapy, DNMTs, Hepatocellular Carcinoma, 5-Aza-CdR, siRNA, CpG islands, methylation

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