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Cellular and Molecular Biology 74: RNA Interference, Small Interfering RNAs, and MicroRNAs: From Mechanism to Cancer Therapeutics

Abstract #6105

Small interfering RNA directed transcriptional activation in human cells

University of California, San Francisco, CA

RNA interference (RNAi) is an evolutionally conserved process in which double-stranded RNA (dsRNA) is processed into 21-25 nucleotide small interfering RNAs (siRNAs) that suppress gene expression by transcriptional and posttranscriptional mechanisms. We have identified a new phenomenon, termed RdTA (RNA directed transcriptional activation), in which siRNA can induce sequence-specific transcriptional activation. We designed and synthesized siRNAs targeting the E-cadherin gene promoter and transfected them into human cancer cells. Our results showed that E-cadherin siRNAs caused dramatic induction of E-cadherin mRNA and protein expression, which subsequently resulted in growth inhibition of transfected cells. These siRNA mediated effects were sequence-specific and long-lasting (at least for ten days following a single transfection). Mechanistically, the induction of E-cadherin was independent of DNA methylation and was associated with decreased histone 3 methylation at lysine 9. These findings suggest a more diverse role for siRNA in regulating genome structure and function than previously recognized and identify a potential therapeutic use for siRNA in cancer treatment through targeted activation of tumor suppressor genes.