The many faces of Dicer: the complexity of the mechanisms regulating Dicer gene expression and enzyme activities

Kurzyńska-Kokorniak, Anna; Koralewska, Natalia; Pokornowska, Maria; Urbanowicz, Anna; Tworak, Aleksander; Mickiewicz, Agnieszka; Figlerowicz, Marek

doi:10.1093/nar/gkv328

Cited by 93 publications

(72 citation statements)

References 195 publications

(273 reference statements)

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“…One post-transcriptional mechanism by which p70 S6K could possibly downregulate the levels of mature miR-145 is by suppressing the maturation of miR-145. Previous reports have demonstrated that Dicer serves as a major regulator of the miRNA biogenesis machinery [26]. Knocking down Dicer clearly abolished the p70 S6K siRNA-mediated suppression of MCS formation (Figure 6B), suggesting a novel link between p70 S6K and Dicer in MCS formation and warrants a closer examination into the mechanism through which p70 S6K regulates Dicer.…”

Section: Resultsmentioning

confidence: 59%

A novel p70 S6 kinase-microRNA biogenesis axis mediates multicellular spheroid formation in ovarian cancer progression

Lam

Mak

et al. 2016

Oncotarget

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Ovarian cancer is the leading cause of death of all gynecologic tumors, associated with widespread peritoneal dissemination and malignant ascites. Key to this is the ability to form multicellular spheroids (MCS); however, the tumor-specific factors that regulate MCS formation are unclear. p70 S6 kinase (p70S6K), which is a downstream effector of phosphatidylinositol 3-kinase/Akt, is frequently constitutively active in ovarian carcinoma. Here we identify p70S6K as a vital regulator of MCS formation. We also uncover a new mechanism of p70S6K function as a component of the microRNA biogenesis machinery in this process. We show that p70S6K phosphorylates, and inhibits the interaction of tristetraprolin (TTP) and Dicer that promotes the expression of a subset of miRNAs, including the maturation of miR-145. Twist and Sox9 are two divergent targets of miR-145, thereby enhancing N-cadherin, but not other cadherin, expression and MCS formation. Activating miR-145 suppresses ovarian tumor growth and metastasis in an orthotopic xenograft mouse model. Meta-analysis in the Oncomine database reveals that high p70S6K and low TTP levels are associated with ovarian tumor progression. These results define a critical link between p70S6K, miRNA maturation, and MCS formation that may underlie poor clinical outcome of ovarian cancer patients for developing novel therapeutic strategies.

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Section: Resultsmentioning

confidence: 59%

A novel p70 S6 kinase-microRNA biogenesis axis mediates multicellular spheroid formation in ovarian cancer progression

Lam

Mak

et al. 2016

Oncotarget

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“…Therefore, the saturation of exportin-5 with pre-miRNAs and some tRNAs decreases the export of Dicer mRNA to the cytoplasm and as a consequence reduces further Dicer gene expression [29]. In addition, recent studies reported that the tumor suppressors p53, p63 and p73 contributed in regulation of Dicer at transcriptional level [30]. Considering all these data, the expression of Dicer regulated with various molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated expression of Dicer in invasive ductal breast carcinoma

et al. 2015

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Several lines of evidence suggest that the global down-regulation of the microRNAome (miRNAome) involved in pathogenesis of various malignancies. Impaired microRNAs processing pathway is one possible mechanism for global down-regulation of the miRNAome. Dicer is a key enzyme in miRNA processing pathway, and dysregulation of its expression has been suggested as a possible cause of miRNAome alterations observed in various cancers. However, Dicer mRNA expression in invasive ductal breast carcinoma (IDC) has not been investigated in depth. Therefore, this study aimed to evaluate the mRNA expression of Dicer in IDC and also to assess the correlation of its expression with clinicopathological parameters including age, histological grade, tumor size and lymph node metastasis. We investigated the expression of the Dicer in seventy fresh invasive ductal breast carcinomas and matched adjacent non-neoplastic tissue by quantitative real-time PCR using validated reference genes. In addition, the possible impact of clinicopathological characteristics on Dicer expression levels was analyzed. Our results showed that Dicer mRNA expression is down-regulated in slightly more than half (51.43 %) of the tumor specimens when compared to adjacent non-neoplastic tissue. Comparison of the Dicer expression level between tumor and matched adjacent non-neoplastic tissue showed that there is no statistical significant differences between them (P = 0.425). We also found that Dicer mRNA expression in IDC samples was not correlated with clinicopathological features. In conclusion, our findings provide additional evidence to support the hypothesis that Dicer expression down-regulated in breast cancer. This study suggested that the decreased expression of Dicer may be potential underlying mechanism in pathogenesis of IDC.

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“…Additionally, Dicer can have various binding partners that influence its activity levels, including TRBP and PACT. 18 It will be important to determine how HDACi treatment affects their ability to interact with Dicer, their regulation of Dicer activity, and their expression levels. Furthermore, we showed that Argonaute-2 was enhanced by Panobinostat treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Dicer, an RNase III endoribonuclease, is responsible for cleaving the pre-miR into a mature miR duplex in the cytoplasm and is indispensable to most miR biogenesis. 18 Upon completion of miR maturation, the mature miR duplex is unwound and the guide strand is loaded onto the RNA-induced silencing complex (RISC). 17 The RISC is responsible for bringing the miR to its target mRNAs, where it binds to the 3 0 UTR and leads to translation inhibition or degradation of the target mRNA.…”

Section: Introductionmentioning

confidence: 99%

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

2017

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microRNAs (miRs) are small noncoding RNAs that regulate/fine tune many cellular protein networks by targeting mRNAs for either degradation or translational inhibition. Dicer, a type III endoribonuclease, is a critical component in miR biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. Recent reports have demonstrated that epigenetic agents, including histone deacetylase inhibitors (HDACi), may regulate Dicer and miR expression. HDACi are a class of epigenetic agents used to treat cancer, viral infections, and inflammatory disorders. However, little is known regarding the epigenetic regulation of miR biogenesis and function. We therefore investigated whether clinically successful HDACi modulated Dicer expression and found that Panobinostat, a clinically approved HDACi, enhanced Dicer expression via posttranscriptional mechanisms. Studies using proteasome inhibitors suggested that Panobinostat regulated the proteasomal degradation of Dicer. Further studies demonstrated that Panobinostat, despite increasing Dicer protein expression, decreased Dicer activity. This suggests that Dicer protein levels do not necessarily correlate with Dicer activity and mature miR levels. Taken together, we present evidence here that Panobinostat posttranscriptionally regulates Dicer/miR biogenesis and suggest Dicer as a potential therapeutic target in cancer.

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The many faces of Dicer: the complexity of the mechanisms regulating Dicer gene expression and enzyme activities

Cited by 93 publications

References 195 publications

A novel p70 S6 kinase-microRNA biogenesis axis mediates multicellular spheroid formation in ovarian cancer progression

A novel p70 S6 kinase-microRNA biogenesis axis mediates multicellular spheroid formation in ovarian cancer progression

Dysregulated expression of Dicer in invasive ductal breast carcinoma

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

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