Inducing gene expression by targeting promoter sequences using small activating RNAs

Wang, Ji; Place, Robert F.; Portnoy, Victoria; Huang, Vera; Kang, Moo Rim; Ho, Maurice K.C.; Li, Long-Cheng

doi:10.14440/jbm.2015.39

Cited by 29 publications

(25 citation statements)

References 46 publications

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“…In a total of 14 DPYSL3v2 promoter-targeted saRNAs, 4 of them showed a significant up-regulation of DPYSL3v2 gene expression at variable levels in multiple prostate cancer cell lines. The targeting sites of the most potent saRNAs on the promoter region are within 1kb range up-stream of the transcription start site and off the CpG island, consistent to published design criteria [17, 20]. These saRNAs induced a significant suppression of cell motility in multiple assays.…”

Section: Discussionsupporting

confidence: 78%

Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis

Jiang

et al. 2016

Oncotarget

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To explore a novel strategy in suppressing tumor metastasis, we took the advantage of a recent RNA activation (RNAa) theory and used small double-strand RNA molecules, termed as small activating RNAs (saRNA) that are complimentary to target gene promoter, to enhance transcription of metastasis suppressor gene. The target gene in this study is Dihydro-pyrimidinase-like 3 (DPYSL3, protein name CRMP4), which was identified as a metastatic suppressor in prostate cancers. There are two transcriptional variants of DPYSL3 gene in human genome, of which the variant 2 is the dominant transcript (DPYSL3v2, CRMP4a) but is also significantly down-regulated in primary prostate cancers. A total of 8 saRNAs for DPYSL3v1 and 14 saRNAs for DPYSL3v2 were tested in multiple prostate cancer cell lines. While none of the saRNAs significantly altered DPYSL3v1 expression, 4 saRNAs showed a strong enhancing effect on DPYSL3v2 expression, resulting in reduced cell mobility in vitro. To achieve a prostate cancer-specific delivery for in vivo testing, we conjugated the most potent saV2-9 RNA molecule with the prostate-specific membrane antigen (PSMA)-targeting aptamer A10-3.2. The conjugates successful increased DPYSL3v2 gene expression in PSMA-positive but not PSMA-negative prostate cancer cells. In nude mice bearing orthotopic xenograft of prostate cancer, a 10-day consecutive treatment with the saV2-9 conjugates significantly suppress distal metastasis compared to the control saRNAs. Analysis of xenograft tissues revealed that DPYSL3v2 expression was largely increased in saV2-9 conjugate-treated group compared to the control group. In conclusion, DPYSL3v2 promoter-targeted saRNA molecules might be used as an adjunctive therapy to suppress prostate cancer metastasis.

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Section: Discussionsupporting

confidence: 78%

Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis

Jiang

et al. 2016

Oncotarget

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“…However, even well-selected dsRNA cannot avoid partial sequence homology to other coding and non-coding sequences ( 27 ). Thus, further research is required to identify whether dsRNA-regulated E-cadherin activation will induce miRNA-like mechanisms of post-transcriptional gene silencing.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of E‑cadherin expression mediated by a novel dsRNA suppresses the growth and metastasis of bladder cancer cells by inhibiting β-catenin/TCF target genes

Liu

Zhang

et al. 2018

Int J Oncol

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Low expression levels of E-cadherin are correlated with poor prognosis in patients with bladder cancer (BCa). A small activating RNA (saRNA) targeting a specific promoter region can activate gene expression. In the present study, two small double-stranded RNAs (dsRNAs) targeting the promoter region of human E-cadherin were designed and synthesized, and the regulatory role of saRNAs in E-cadherin expression was investigated. The results of reverse transcription-quantitative polymerase chain reaction and western blotting demonstrated that transfection of dsEcad-346 into the BCa cell lines T24 and 5637 significantly activated E-cadherin expression. Furthermore, transfection of dsEcad-346 and miR-373 induced cell cycle arrest in G0/G1 phase, promoted apoptosis and significantly inhibited migration and invasion of BCa cells. Results of immunofluorescence and western blotting indicated that β-catenin was redistributed from the nucleus to the cell membrane following transfection of dsEcad-346 and miR-373. Additionally, the expression of β-catenin/T-cell factor complex (TCF) target genes (c-MYC, matrix metallopeptidase 2, cyclin D1) was suppressed following transfection of BCa cells with saRNA. Silencing of E-cadherin expression blocked the inhibitory effect of dsEcad-346 and miR-373 on BCa cells. In conclusion, a novel designed dsEcad-346 can activate the expression of E-cadherin in BCa cells. saRNA-mediated activation of E-cadherin expression inhibited the growth and metastasis of BCa cells by promoting the redistribution of β-catenin from nucleus to cell membrane and inhibiting the β-catenin/TCF target genes.

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“…Small double-stranded RNAs (dsRNAs) induced RNA activation (RNAa) is a novel approach of gene activation that has been studied gradually (Pan et al, 2013;Lopez et al, 2016). This class of dsRNA is named small activating RNA (saRNA), which binds to gene promoter sequences and leads to changes in chromatin structure and transcriptional activation (Place et al, 2008;Schwartz et al, 2008;Wang et al, 2015a). Various saRNAs have been shown to activate a number of important genes, including NANOG (Wang et al, 2012), KLF4 (Wang et al, 2010;Voutila et al, 2012), c-MYC (Voutila et al, 2012) etc.…”

Section: Introductionmentioning

confidence: 99%

Activation of KLF4 expression by small activating RNA promotes migration and invasion in colorectal epithelial cells

Zhou

Fan

Huang

et al. 2018

Cell Biology International

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RNA activation mediated by small double-stranded RNAs targeting promoter sequence named small activating RNAs (saRNAs) is one of the mechanisms for gene activation. Artificial regulation of gene expression through RNA activation does not affect the alteration of the genomic DNA sequences or exogenous plasmid DNA, therefore it is a relative manageable approach for gene perturbation. KLF4 is a member of zinc-finger transcription factors and its functions in colorectal cells are still controversial. In order to elucidate the functions of KLF4, we synthesized saRNAs that target the promoter regions of KLF4 and transfected into varied colorectal epithelial cell lines. We found the KLF4 gene expression is specifically increased in the human normal epithelial cell NCM460 and colorectal epithelial cancer cell Caco-2 and HCT116, but not in other human colorectal epithelial cell lines. In addition, we observed that saRNAs induced overexpression of KLF4 could promote cell migration/invasion in NCM460 and HCT116 cell lines. This effect is mediated partly by inducing EMT and facilitating nuclear translocation of β-catenin.

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Inducing gene expression by targeting promoter sequences using small activating RNAs

Cited by 29 publications

References 46 publications

Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis

Enhancing DPYSL3 gene expression via a promoter-targeted small activating RNA approach suppresses cancer cell motility and metastasis

Upregulation of E‑cadherin expression mediated by a novel dsRNA suppresses the growth and metastasis of bladder cancer cells by inhibiting β-catenin/TCF target genes

Activation of KLF4 expression by small activating RNA promotes migration and invasion in colorectal epithelial cells

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