Promoter-targeted double-stranded small RNAs activate PAWR gene expression in human cancer cells

Yang, Kai; Shen, Jie; Xie, Yanqi; Lin, Yiwei; Qin, Jie; Mao, Qinan; Zheng, Xiangyi; Xie, Liping

doi:10.1016/j.biocel.2013.03.022

Cited by 29 publications

(38 citation statements)

References 39 publications

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“…RNAa is triggered by small RNAs that target gene promoters and induce the transcription of mRNA, exerting the opposite effect of RNAi. Previous studies have validated that RNAa is able to induce robust and prolonged expression of tumor suppressor genes and thus leads to antigrowth effects in vitro and in vivo in various cancer cells 11, 12, 15. Intravesical or rectal delivery of small RNAs preferentially accumulated at the tumor site and demonstrated excellent antitumor activity,21, 22 which provided a preclinical proof of concept for novel cancer therapy.…”

Section: Discussionmentioning

confidence: 97%

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RNAa and Vector-Mediated Overexpression of DIRAS1 Suppresses Tumor Growth and Migration in Renal Cell Carcinoma

Wang

et al. 2018

Molecular Therapy - Nucleic Acids

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The downregulation of DIRAS1 has been suggested to potentially contribute to tumor development and progression in several human cancers. However, the role of DIRAS1 in renal cell carcinoma (RCC) remains elusive. In this study, we examined the DIRAS1 expression level in RCC cell lines and tissues. Both RNA activation (RNAa) and vector transfection methods were used to upregulate the expression of DIRAS1 in RCC cells. Expression analysis revealed that DIRAS1 was significantly downregulated in RCC cell lines and tissues compared with nontumorigenic renal cells and adjacent nontumor tissues individually. Promoter methylation analysis indicated that the reduced DIRAS1 expression might be partly mediated by epigenetic modulation. The RNAa-mediated overexpression of DIRAS1 inhibited cell proliferation and tumorigenicity in vitro and in vivo. The re-activation of DIRAS1 also promoted apoptosis and suppressed migration and invasion in RCC cells. The ectopic expression of DIRAS1 via an expression vector recapitulated the RNAa results. These results reveal that DIRAS1, functioning as a putative tumor suppressor in RCC cells, could potentially be a therapeutic target and RNAa could be a therapeutic strategy for RCC.

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Section: Discussionmentioning

confidence: 97%

“…The RNAa technique has been widely used to upregulate tumor suppressor genes, including p21, 11 NKX3-1, 14 PAWR, 15 and E-cadherin, 16 in various human cancers. RNAa is a promising discovery and represents a novel approach to gene overexpression, in addition to traditional vector-based systems.…”

Section: Introductionmentioning

confidence: 99%

RNAa and Vector-Mediated Overexpression of DIRAS1 Suppresses Tumor Growth and Migration in Renal Cell Carcinoma

Wang

et al. 2018

Molecular Therapy - Nucleic Acids

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“…The causative relation between ras, MAPK/ERK and Par-4 was confirmed: Inhibition of MEK causes downregulation of both the DNA-methylases whereon the function of the Par-4 promoter is restored and the Par-4-activity raises again [42, 43]. …”

Section: Supportive Evidencementioning

confidence: 99%

“…In animal experiments intravenous injection of recombinant Par-4 was sufficient to inhibit the formation of metastases [56]. Yang et colleagues noticed that in vitro activation of Par-4-expression by small activating RNA (saRNA) induced growth inhibition and apoptosis in tumor cells [42]. …”

Section: Supportive Evidencementioning

confidence: 99%

Simultaneous dual targeting of Par-4 and G6PD: a promising new approach in cancer therapy? Quintessence of a literature review on survival requirements of tumor cells

Cernaj¹

2016

Cancer Cell Int

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The aim of this hypothesis is to propose a new approach in targeted therapy of cancer: The simultaneous, dual targeting of two single molecules, Par-4 and G6PD, rather than inhibition of full-length signaling pathways. Rationale: Targeted inhibition of especially two survival signaling pathways (PI3K/AKT/mTOR and MAPK/ERK) is frequently tried, however, a major breakthrough has not yet been reported. Inhibition of complete pathways naturally goes along with a variety of dose-limiting side effects thus contributing to poor efficacy of the administered drugs. This essay offers a synopsis of relevant studies to support the above mentioned idea—targeting of two single molecules which either are crucial for tumor growth and cancer-cell-survival: on one side, Par-4-activation selectively triggers apoptosis of tumor cells thus reversing their characteristic feature—immortality. On the other side inhibition of G6PD breaks the energy supply of tumor cells, weakens their defence against oxidative stress and thereby enhances the sensitivity of tumor cells to oxidative agents (e.g. chemotherapy). Advantage of the proposed dual Par-4/G6PD-therapy is good tolerability and—especially when administered along with conventional therapy—less frequent emergence of resistance.

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“…75 Subsequently, there are many more reports of small-RNA directed RNAa, including by groups also demonstrating TGS ( Table 2 ). 29,51,54,64,65,72,76,77,78,79,80,81,82,83,84,85,86,87,88,89 …”

Section: Exogenous Small Rna Transcriptional Silencing and Activationmentioning

confidence: 99%

The Varied Roles of Nuclear Argonaute-Small RNA Complexes and Avenues for Therapy

Ross

Kassir

2014

Molecular Therapy - Nucleic Acids

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Argonautes are highly conserved proteins found in almost all eukaryotes and some bacteria and archaea. In humans, there are eight argonaute proteins evenly distributed across two clades, the Ago clade (AGO1-4) and the Piwi clade (PIWIL1-4). The function of Ago proteins is best characterized by their role in RNA interference (RNAi) and cytoplasmic post-transcriptional gene silencing (PTGS) – which involves the loading of siRNA or miRNA into argonaute to direct silencing of genes at the posttranscriptional or translational level. However, nuclear-localized, as opposed to cytoplasmic, argonaute-small RNA complexes may also orchestrate the mechanistically very different process of transcriptional gene silencing, which results in prevention of transcription from a gene locus by the formation of silent chromatin domains. More recently, the role of argonaute in other aspects of epigenetic regulation of chromatin, alternative splicing and DNA repair is emerging. This review focuses on the activity of nuclear-localized short RNA-argonaute complexes in a mammalian setting and discusses recent in vivo studies employing nuclear-directed sRNA for therapeutic interventions. These studies heed the potential development of RNA-based drugs which induce epigenetic changes in the cell.

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Promoter-targeted double-stranded small RNAs activate PAWR gene expression in human cancer cells

Cited by 29 publications

References 39 publications

RNAa and Vector-Mediated Overexpression of DIRAS1 Suppresses Tumor Growth and Migration in Renal Cell Carcinoma

RNAa and Vector-Mediated Overexpression of DIRAS1 Suppresses Tumor Growth and Migration in Renal Cell Carcinoma

Simultaneous dual targeting of Par-4 and G6PD: a promising new approach in cancer therapy? Quintessence of a literature review on survival requirements of tumor cells

The Varied Roles of Nuclear Argonaute-Small RNA Complexes and Avenues for Therapy

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