Aberrant epigenetic modifications in the CTCF binding domain of the IGF2/H19 gene in prostate cancer compared with benign prostate hyperplasia

Paradowska, Agnieszka; Fenic, Irina; Konrad, Lutz; Sturm, Klaus; Wagenlehner, Florian; Weidner, W.; Steger, Klaus

doi:10.3892/ijo_00000316

Cited by 30 publications

(22 citation statements)

References 29 publications

(33 reference statements)

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“…This local hypomethylation suggests a tight regulatory mechanism that is most likely mediated by locusspecific recruitment of DNA-modifying or binding factors that protect DNA from methylation by DNA methyltransferases. Such tumor-specific regulation of CTCF-binding sites by methylation is known (27). It has even been shown that CTCF itself can regulate DNA methylation patterns and that cancerous or immortalized cells, when compared with normal cells, have a distinct CTCFbinding landscape in the genome (28), highlighting the complexity of methylation-related regulation, especially when addressed in a locus-specific manner.…”

Section: Pace4 Splicing Is Regulated By Intraexonic Dna Methylationmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3 0 untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. Ó2017 AACR.

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Section: Pace4 Splicing Is Regulated By Intraexonic Dna Methylationmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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“…IGF2 expression is elevated in ovarian, colorectal and breast cancer associated with poor prognosis (Cardillo et al 2003, Sayer et al 2005, Kalla Singh et al 2007, Pollak 2008a, Huang et al 2010 and increased cell motility (Diaz et al 2007). Dysregulated expression of IGF2 in PC tumours and in surrounding prostate and stromal tissue occurs partially through loss of imprinting (Van Roozendaal et al 1998, Cui et al 2003, Poirier et al 2003, Bhusari et al 2011, Wang et al 2011 and correlates with tumour vs benign hyperplasia (Paradowska et al 2009); however, tumour IGF2 expression levels are not reflected in serum (Rowlands et al 2009(Rowlands et al , 2012. IGF2 can signal through the IGF1 receptor (IGF1R) or via the insulin receptor (INSR) to elicit insulin-like signalling (Cardillo et al 2003, Pandini et al 2004.…”

Section: Introductionmentioning

confidence: 99%

IGF2 increases de novo steroidogenesis in prostate cancer cells

Lubik¹,

Gunter²,

Hollier³

et al. 2013

Endocrine-Related Cancer

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IGF2 is a mitogenic foetal growth factor commonly over-expressed in cancers, including prostate cancer (PC). We recently demonstrated that insulin can activate de novo steroidogenesis in PC cells, a major pathway for reactivation of androgen pathways and PC progression. IGF2 can activate the IGF1 receptor (IGF1R) or insulin receptor (INSR) or hybrids of these two receptors. We therefore hypothesized that IGF2 may contribute to PC progression via de novo steroidogenesis. IGF2 mRNA but not IGF2 receptor mRNA expression was increased in patient samples during progression to castrate-resistant PC as was immunoreactivity to INSR and IGF1R antibodies. Treatment of androgen receptor (AR)-positive PC cell lines LNCaP and 22RV1 with IGF2 for 48 h resulted in increased expression of steroidogenic enzyme mRNA and protein, including steroid acute regulatory protein (StAR), cytochrome p450 family member (CYP)17A1, aldo-keto reductase family member (AKR)1C3 and hydroxysteroid dehydrogenase (HSD)17B3. IGF2 treatment resulted in increased steady state steroid levels and increased de novo steroidogenesis resulting in AR activation as demonstrated by PSA mRNA induction. Inhibition of the IGF1R/INSR signalling axis attenuated the effects of IGF2 on steroid hormone synthesis. We present a potential mechanism for prostatic IGF2 contributing to PC progression by inducing steroidogenesis and that IGF2 signalling and related pathways present attractive targets for PC therapy.

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“…2A), immediately upstream of the miR-483 stem loop, has strong insulator activity and binds to the CTCF repressor (22). CTCF is an important methyl-sensitive regulator of transcription involved in the epigenetic regulation of genomic imprinted loci such as the IGF2/H19 locus in 11p15.5, and is involved in Wilms' tumor (23,24), breast cancer (25,26), and prostate cancer (27). We decided to determine whether CTCF is also involved in the repression of the IGF2/mir-483 genomic regions we cloned.…”

Section: Zinc Finger Ccctc-binding Factor Ctcf Represses the Genomic mentioning

confidence: 99%

Mutated β-catenin evades a microRNA-dependent regulatory loop

Veronese

Visone

Consiglio

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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hsa-mir-483 is located within intron 2 of the IGF2 gene. We have previously shown oncogenic features of miR-483-3p through cooperation with IGF2 or by independently targeting the proapoptotic gene BBC3/PUMA. Here we demonstrate that expression of miR-483 can be induced independently of IGF2 by the oncoprotein β-catenin through an interaction with the basic helix-loop-helix protein upstream stimulatory transcription factor 1. We also show that β-catenin itself is a target of miR-483-3p, triggering a negative regulatory loop that becomes ineffective in cells harboring an activating mutation of β-catenin. These results provide insights into the complex regulation of the IGF2/miR-483 locus, revealing players in the β-catenin pathway.T he multifunctional protein β-catenin is involved in cell-cell adhesion when it is localized to the cellular membrane (1), and in transcriptional regulation by translocation into the nucleus through the Wnt pathway (2). Wnt signaling is an important molecular pathway required for cellular differentiation, tissue homeostasis, and tissue morphogenesis. Wnt/β-catenin signaling is one of the most commonly activated pathways in cancer, and several Wnt signaling-related gene mutations have been described: adenomatous polyposis coli (APC) and protein phosphatase 2 regulatory subunit A (PPP2R1B) mutations in colorectal cancer (3), AXIN1 mutation in hepatocarcinoma (4), and WTX gene mutations in Wilms' tumor (5), and β-catenin gene (CTNNB1) itself was shown to be mutated (6-8) in the amino-terminal region used for degradation by the GSK3β-APC-AXIN-WTX complex (5, 9). These mutations prevent β-catenin degradation and result in its accumulation in the nucleus, where it acts as a specific transcriptional coactivator of the DNA-binding T-cell factor/lymphoid enhancer factor protein family. Among the targets of this family are important genes involved in tumorigenesis such as MYC, CCND1, CJUN, and FRA1 (10, 11).MicroRNAs (miRNAs) are small noncoding RNAs that modulate gene expression by base pairing to target messenger RNAs (mRNAs) and by inhibiting their translation and/or promoting their degradation (12). MicroRNAs play a critical role in the normal maintenance of fundamental cellular processes, and their deregulation in human neoplasm has been proven to affect a large number of molecular pathways related to cancer (13)(14)(15).Because the miR-483 locus is dysregulated in tumors involving the β-catenin pathway (16-18), we investigated their possible connection.Results miR-483-3p Expression Correlates with the Mutational Status of Wnt/ β-Catenin Genes in Hepatocarcinoma. The Wnt/β-catenin pathway is one of the most important pathways dysregulated in hepatocarcinoma (HCC), colorectal cancer (CRC), and Wilms' tumor (19-21). Because we previously found that miR-483-3p, which is located in intron 2 of the IGF2 gene, is up-regulated in these cancers as well, we investigated the possible involvement of Wnt/β-catenin in miR-483-3p dysregulation.We previously found a positive coefficient of correlation (R) ...

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Aberrant epigenetic modifications in the CTCF binding domain of the IGF2/H19 gene in prostate cancer compared with benign prostate hyperplasia

Cited by 30 publications

References 29 publications

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

IGF2 increases de novo steroidogenesis in prostate cancer cells

Mutated β-catenin evades a microRNA-dependent regulatory loop

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