Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells

Kitchen, Mark; Yacqub-Usman, Kiren; Emes, Richard D.; Richardson, Alan; Clayton, Richard N.; Farrell, William E.

doi:10.1007/s11102-014-0630-5

Cited by 16 publications

(10 citation statements)

References 52 publications

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“…Previous work has demonstrated that let-7 targets the HMGA 3= UTRs to promote transcript degradation (32). In agreement with our data, overexpression or upregulation of let-7 in GH3 cells decreases HMGA1 mRNA and attenuates cellular proliferation in a timedependent manner (27,32,45). Our work suggests that miR-29c may also target HMGA-1 given that the antagomir to miR-29c prevents HMGA1 repression.…”

Section: Figsupporting

confidence: 92%

“…For example, DNA hypermethylation decreases let-7 and miR-23b expression and subsequently contributes to tumorigenesis (43,44). In contrast, treatment of pituitary cells with the DNA methyltransferase inhibitor zebularine and the histone deacetylase inhibitor trichostatin A slows proliferation by inducing the reexpression of oncogenetargeting miRNAs (45). Our work shows that PAD-catalyzed histone citrullination represses tumor suppressor miRNA expression, which is potentially important in PA etiology.…”

Section: Figmentioning

confidence: 75%

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Histone Citrullination Represses MicroRNA Expression, Resulting in Increased Oncogene mRNAs in Somatolactotrope Cells

DeVore

Young

et al. 2018

Molecular and Cellular Biology

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Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas is unknown. To begin to address these questions, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4 and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA-sequencing and ChIP studies show that the expression of microRNAs let-7c-2, miR-23b and miR-29c is suppressed by histone citrullination. Our studies demonstrate that these miRNAs directly target the mRNA of the oncogenes HMGA, IGF-1 and N-MYC, which are highly implicated in human prolactinoma/somatoprolactinoma pathogenesis. Our results are the first to define a direct role for PAD catalyzed histone citrullination in miRNA expression, which may underlie the etiology of prolactinoma and somatoprolactinoma tumors through regulation of oncogene expression.

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Section: Figsupporting

confidence: 92%

Section: Figmentioning

confidence: 75%

Histone Citrullination Represses MicroRNA Expression, Resulting in Increased Oncogene mRNAs in Somatolactotrope Cells

DeVore

Young

et al. 2018

Molecular and Cellular Biology

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“…Similarly, overexpression of high mobility group A (HMGA) genes, a frequent finding in pituitary adenomas, results from epigenetic changes that downregulate microRNA targeting HMGA genes. Epidrugs also revert these modifications [121]. The clinical implications of these findings remain to be determined.…”

Section: Pituitary Tumor Epigeneticsmentioning

confidence: 89%

Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature—“Are We There Yet?”

Lamb

Sim

McCormack

2020

Cancers

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Aggressive pituitary tumors account for up to 10% of pituitary tumors and are characterized by resistance to medical treatment and multiple recurrences despite standard therapies, including surgery, radiotherapy, and chemotherapy. They are associated with increased morbidity and mortality, particularly pituitary carcinomas, which have mortality rates of up to 66% at 1 year after diagnosis. Novel targeted therapies under investigation include mammalian target of rapamycin (mTOR), tyrosine kinase, and vascular endothelial growth factor (VEGF) inhibitors. More recently, immune checkpoint inhibitors have been proposed as a potential treatment option for pituitary tumors. An increased understanding of the molecular pathogenesis of aggressive pituitary tumors is required to identify potential biomarkers and therapeutic targets. This review discusses novel approaches to the management of aggressive pituitary tumors and the role of molecular profiling.

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“…Relative quantification of transcript expression was performed using the 2 ¡DDCT method, 75 as previously described. 76 Reduced transcript expression in a tumor was defined where expression was at least 3-fold lower than the mean level of expression observed in control samples; the converse was true for increased transcript expression. 37,38,77 Non-array informatics and statistics STATA (version 8, Stata Corporation, College Station, TX) was used to analyze methylation and gene expression data in tumor and normal cohorts using Fisher's exact tests (frequency of methylation), Student's t-tests (mean level of methylation), and Spearman correlation coefficients (associations between methylation and gene expression).…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

Kitchen¹,

Bryan²,

Emes³

et al. 2016

European Urology Supplements

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High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterize this disease entity in the context of tumor development, recurrence, and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip arrays in 21 primary HG-NMIBC tumors relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. We validated the array data by bisulphite pyrosequencing and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumors relative to lowintermediate-grade tumors for the ATP5G2, IRX1 and VAX2 genes (P<0.05), and similarly significant increases in mean levels of methylation in high-grade tumors for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (P<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumors. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease.

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Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells

Cited by 16 publications

References 52 publications

Histone Citrullination Represses MicroRNA Expression, Resulting in Increased Oncogene mRNAs in Somatolactotrope Cells

Histone Citrullination Represses MicroRNA Expression, Resulting in Increased Oncogene mRNAs in Somatolactotrope Cells

Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature—“Are We There Yet?”

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

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