MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence

Cho, Joon-Ho; Dimri, Manjari; Dimri, Goberdhan P.

doi:10.1074/jbc.m114.624361

Cited by 73 publications

(58 citation statements)

References 56 publications

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“…10,11,13,14 Altered expression and/or recruitment of HDACs have been shown to contribute to dysregulation of specific miRNA (e.g., miR-29, miR-200b, miR-31, miR-125a, miR-125b and miR-205) in human breast and lung cancers. [5][6][7][8] Our data show that treatment with Depsi (class I HDAC inhibitor), SAHA (pan-HDAC inhibitor) or 966 (HDAC3-selective inhibitor) resulted in elevated levels of mature miRNA of the miR-15 and let-7 families. This increase in miRNA expression was selective as not all miRNA assessed were induced by HDACi.…”

Section: Discussionmentioning

confidence: 73%

“…One such mechanism that has been linked to HDAC regulation includes microRNA (miRNA). [5][6][7][8] miRNA comprise a class of noncoding RNA that post-transcriptionally regulate the expression of target mRNA, typically resulting in decreased translation. 9 The potential for miRNA-guided regulation of gene expression is significant, as it is predicted that the majority of all mRNAs are under miRNA control and that a single miRNA can target many mRNA.…”

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confidence: 99%

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Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

Adams

Eischen

2016

Cell Death Differ

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Histone deacetylase (HDAC) inhibition leads to dynamic changes in the epigenetic landscape that is postulated to alter the expression of critical mediators of cellular proliferation and death. While current HDAC inhibitors have shown to be efficacious in the treatment of specific hematologic malignancies, their therapeutic utility in epithelial-based cancers warrants further evaluation. Moreover, the mechanisms of HDAC inhibition-induced cancer cell death are not completely understood. Therefore, elucidation of the underlying pathways engaged by HDAC inhibition may enable the development of more effective therapeutic strategies. Here, we report that HDAC inhibition in human breast and lung carcinoma cells activates an apoptotic mechanism mediated by microRNA (miRNA) and induced by the oncogene MYC. Specifically, following HDAC inhibition, MYC, which normally represses miR-15 and let-7 families, transcriptionally activated their expression and MYC was required for this miRNA upregulation. As a result, transcript levels of the tumor-suppressive miR-15 and let-7 families increased, which targeted and decreased the expression of the crucial prosurvival genes BCL-2 and BCL-X L , respectively. MYC was also required for the downregulation of BCL-2 and BCL-X L following HDAC inhibition. Blocking the binding sites of the miR-15 and let-7 families in the 3′-untranslated regions of BCL-2 and BCL-X L protected against HDAC inhibition-induced apoptosis. These results provide important insight into the molecular underpinnings of HDAC inhibition-induced cell death in breast and lung cancer and reveal a tumor-suppressive role for MYCregulated miRNA that is activated with HDAC inhibition.

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Section: Discussionmentioning

confidence: 73%

mentioning

confidence: 99%

Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

Adams

Eischen

2016

Cell Death Differ

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“…In addition, miR‐31a‐5p has been reported to directly target bone relevant markers, such as RUNX2, OSX, and DKK1 (Baglio, Devescovi, Granchi, & Baldini, 2013; Deng, Wu et al., 2013; Gao et al., 2011; Lv et al., 2017). Furthermore, it has been reported that regulation of miR‐31a‐5p expression could be used to modulate senescence‐related pathological conditions such as cancer, and the aging process (Capri et al., 2017; Cho, Dimri, & Dimri, 2015), which highlights us the important role of miR‐31a‐5p in cellular senescence. Moreover, according to a previous study, miR‐31a‐5p controls osteoclast formation and facilitates IL‐2 production in T cells by targeting RhoA (Fan et al., 2012; Mizoguchi, Murakami, Saito, Miyasaka, & Kohsaka, 2013).…”

Section: Introductionmentioning

confidence: 87%

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

et al. 2018

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The alteration of age‐related molecules in the bone marrow microenvironment is one of the driving forces in osteoporosis. These molecules inhibit bone formation and promote bone resorption by regulating osteoblastic and osteoclastic activity, contributing to age‐related bone loss. Here, we observed that the level of microRNA‐31a‐5p (miR‐31a‐5p) was significantly increased in bone marrow stromal cells (BMSCs) from aged rats, and these BMSCs demonstrated increased adipogenesis and aging phenotypes as well as decreased osteogenesis and stemness. We used the gain‐of‐function and knockdown approach to delineate the roles of miR‐31a‐5p in osteogenic differentiation by assessing the decrease of special AT‐rich sequence‐binding protein 2 (SATB2) levels and the aging of BMSCs by regulating the decline of E2F2 and recruiting senescence‐associated heterochromatin foci (SAHF). Notably, expression of miR‐31a‐5p, which promotes osteoclastogenesis and bone resorption, was markedly higher in BMSCs‐derived exosomes from aged rats compared to those from young rats, and suppression of exosomal miR‐31a‐5p inhibited the differentiation and function of osteoclasts, as shown by elevated RhoA activity. Moreover, using antagomiR‐31a‐5p, we observed that, in the bone marrow microenvironment, inhibition of miR‐31a‐5p prevented bone loss and decreased the osteoclastic activity of aged rats. Collectively, our results reveal that miR‐31a‐5p acts as a key modulator in the age‐related bone marrow microenvironment by influencing osteoblastic and osteoclastic differentiation and that it may be a potential therapeutic target for age‐related osteoporosis.

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“…Previously, it was shown that HDACi treatment could rapidly alter miR expression levels, either increasing or decreasing certain subsets of micro-RNA. [50][51][52][53] Future studies should include dissecting how and why HDACi differentially regulate the expression of miR subsets. Investigating whether different classes of HDACi affect miR expression similarly may lead to a better understanding of HDACi treatments and the epigenetic regulation of miRs.…”

Section: Discussionmentioning

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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MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence

Cited by 73 publications

References 56 publications

Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

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