Activation of microRNA inhibits cancer gene in human cancer cells

Scientists report that tumor cells display a dramatic reduction of cancer-causing genes when a newly discovered method is used to activate the expression of protective microRNAs in the cancer cell genome. The research, published in the June issue of Cancer Cell, demonstrates that agents known to regulate gene expression can also impact regulatory RNAs that may function as tumor suppressors in normal cells and proposes a novel strategy for treating human cancers.

DNA methylation and histone deacetylation are epigenetic processes involved in the regulation of gene expression. In the case of cancer, these processes are thought to turn off genes that may protect cells from abnormal cell growth. Drugs that inhibit DNA methylation and histone deacetylation, known as chromatin-modifying drugs, can reactivate genes that have been abnormally silenced in cancer cells. It is conceivable that these processes may also regulate expression of some RNAs.

MicroRNA (miRNA) is small and noncoding RNA that can regulate gene expression by inhibiting protein translation. Recent research has implicated miRNAs in cancer development and has led to the observation that some miRNAs are reduced in various human cancers and may normally function as tumor suppressors. According to study author Dr. Peter A. Jones from the Norris Comprehensive Cancer Center at the University of Southern California in Los Angeles, "Although the biological importance of miRNA is becoming increasingly apparent, regulation of miRNA expression is not fully understood."

Dr. Jones and his colleagues examined whether miRNAs can be controlled by epigenetic alterations linked to chromatin remodeling. Cancer cells and normal cells were treated with chromatin-remodeling drugs to simultaneously inhibit DNA methylation and histone deacetylation. A subset of miRNAs was upregulated in the cancer cells but not the normal cells. Importantly, miR-127, which is downregulated in 75% of the human cancer cells tested, was highly induced after treatment with the chromatin-remodeling drugs. Induction of miR-127 resulted in downregulation of BCL6, a known proto-oncogene. Therefore, induction of miR-127 by treatment with chromatin-remodeling drugs may have an anticancer effect.

"Taken together, our results suggest an effect of epigenetic treatment that couples inhibitors of DNA methylation and histone deacetylation to induction of some miRNAs. These miRNAs can potentially regulate expression of target genes that are important in the development and progression of human cancer. Further studies on epigenetic regulation of miRNA expression are necessary, and regulation of miRNA expression by epigenetic treatment may be a novel strategy for prevention or treatment of human cancer," offers Dr. Jones.

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The researchers include Yoshimasa Saito, Gangning Liang, Gerda Egger, Jeffrey M. Friedman, Jody C. Chuang, Gerhard A. Coetzee, and Peter A. Jones of Norris Comprehensive Cancer Center, University of Southern California in Los Angeles, CA. This work was supported by grants from the National Institutes of Health (RO1 CA 82422 to P.A.J.), the Department of Defense (W81XWH-04-1-0823 to G.A.C.), the Uehara Memorial Foundation of Japan (Y.S.), and the Max Kade Foundation (G.E.). Saito et al.: "Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells." Publishing in Cancer Cell 9, 435443, June 2006. DOI 10.1016/j.ccr.2006.04.020 www.cancercell.org


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