30 research outputs found
Abstract 488: Reprogramming cancer cells into terminal differentiation via induced pluripotency
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Hiwi mediated tumorigenesis is associated with DNA hypermethylation.
No full textExpression of Piwi proteins is confined to early development and stem cells during which they suppress transposon migration via DNA methylation to ensure genomic stability. Piwi's genomic protective function conflicts with reports that its human ortholog, Hiwi, is expressed in numerous cancers and prognosticates shorter survival. However, the role of Hiwi in tumorigenesis has not been examined. Here we demonstrate that (1) over-expressing Hiwi in sarcoma precursors inhibits their differentiation in vitro and generates sarcomas in vivo; (2) transgenic mice expressing Hiwi (mesodermally restricted) develop sarcomas; and (3) inducible down-regulation of Hiwi in human sarcomas inhibits growth and re-establishes differentiation. Our data indicates that Hiwi is directly tumorigenic and Hiwi-expressing cancers may be addicted to Hiwi expression. We further show that Hiwi associated DNA methylation and cyclin-dependent kinase inhibitor (CDKI) silencing is reversible along with Hiwi-induced tumorigenesis, via DNA-methyltransferase inhibitors. Our studies reveal for the first time not only a novel oncogenic role for Hiwi as a driver of tumorigenesis, but also suggest that the use of epigenetic agents may be clinically beneficial for treatment of tumors that express Hiwi. Additionally, our data showing that Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis
Russian prefixes and prepositions in Stratal OT
No full textSince the work of Zubritskaya (1995) and Matushansky (2002), it has been known that prefixes and prepositions instantiate a synchronically unified and unique class in Russian phonology. A less discussed point is that Russian prefixes and prepositions cannot be unified on the basis of their morphosyntactic characteristics. An existing analysis (Rubach 2000) addresses only the phonological facts, implicitly assuming that the two categories are identical morphosyntactically. To resolve the apparent contradiction between the phonological identity and the morphosyntactic nonidentity of prefixes and prepositions, I propose a Stratal OT (Kiparsky 2000) approach to the jer vocalization and palatalization patterns within the complex containing the prefix/preposition and its host. The account takes as its foundation the work of Blumenfeld (2003), and posits that prefixes and prepositions are processed at distinct strata (word and postlexical, respectively). The paper also provides tentative evidence, based on jer realization patterns, to support the claim that there is a phonological, not just morphosyntactic, reason to associate the composition of prefixes and prepositions with different strata.This is the authors' draft version of the paper. The definitive version of this paper is published in Proceedings of the 26th West Coast Conference on Formal Linguistics (2008) and is a available at http://www.lingref.com/cpp/wccfl/26/abstract1675.htmlGrobanova, V. (2008). Russian prefixes, prepositions and palatalization in Stratal OT. In C.B. Chang & H.J. aynie (Eds.) Proceedings of the 26th West Coast Conference on Formal Linguistics (pp. 217-225). Somerville, MA, USA: Cascadilla Proceedings Project.ISBN 978-1-57473-423-2 (published conference proceedings
Chromatin Structure Predicts Epigenetic Therapy Responsiveness in Sarcoma
No full textAbstract
To formally explore the potential therapeutic effect of histone deacetylase inhibitors (HDACI) and DNA-methyltransferase inhibitors (DNA-MI) on sarcomas, we treated a large sarcoma cell line panel with five different HDACIs in the absence and presence of the DNA-MI decitabine. We observed that the IC50 value of each HDACI was consistent for all cell lines whereas decitabine as a single agent showed no growth inhibition at standard doses. Combination HDACI/DNA-MI therapy showed a preferential synergism for specific sarcoma cell lines. Subsequently, we identified and validated (in vitro and in vivo) a two-gene set signature (high CUGBP2; low RHOJ) that associated with the synergistic phenotype. We further uncover that the epigenetic synergism leading to specific upregulation of CDKI p21 in specific cell lines is a function of the differences in the degree of baseline chromatin modification. Finally, we show that these chromatin and gene expression patterns are similarly present in the majority of high-grade primary sarcomas. Our results provide the first demonstration of a gene set that can predict responsiveness to HDACI/DNA-MI and links this responsiveness mechanistically to the baseline chromatin structure. Mol Cancer Ther; 10(2); 313–24. ©2011 AACR.</jats:p
Assessment of Hiwi target genes.
No full text<p>(A) Top panel: Affymetrix 430 2.0 array of gene expression changes in parental MSCs (x-axis) or Hiwi-MSCs (y-axis). Affymetrix U433 array of gene expression changes in sh-Hiwi MFH cells uninduced (x-axis) or induced for 7 days with doxycycline (y-axis) (middle panel) or untreated (x-axis) and after 7 days of 1 uM 5-azacytidine (y-axis) (bottom panel). Arrow indicates genes used in overlap analysis. (B) Overlap of Tumor Suppressor Genes (TSG) as described. All 19 overlapping TSGs are listed here.</p
Hiwi down-regulation and 5-azacytidine treatment are mechanistically similar.
No full text<p>(A) Gene expression profiles of sh-Hiwi MFH cells treated with 1 uM or 5 uM 5-azacytidine cluster with gene expression profiles of doxycycline-induced sh-Hiwi MFH cells, using the whole gene set from both treatments. (B) Meth27 Illumina array of methylation of 27000 CpG site changes in sh-Hiwi MFH cells uninduced (x-axis) or induced with doxycycline for 7 days (y-axis). Graph shows all CpG islands and reveals no global shift in CpG methylation.</p
Hiwi expression correlates with DNA methylation.
No full text<p>(A) IAP and Line1 transposon expression is decreased in Hiwi-MSCs. IAP and Line1 semi-quantitative PCRs were run for 25 cycles. Actin is a loading control. (B) Global DNA methylation is increased in Hiwi-MSCs. Error bars represent standard error. * = p<0.05 by Student's T Test (C) Global DNA methylation is decreased to non-detectable levels (ND) after 18 h treatment with 10 uM 5-azacytidine in Hiwi-MSCs. Lower doses of 5-azacytidine (including 1 uM) did not change DNA methylation levels. Error bars represent standard error * = p<0.05 by Student's T Test (D) Western blots of indicated proteins reveal increased expression of DNMT1, DNMT3a and MBP2 in Hiwi-MSCs. Actin is a loading control. (E) Treatment of Hiwi expressing MSCs with 0 uM, 5 uM, 10 uM, or 50 uM 5-azacytidine for 18 h restores IAP and Line1 transposon expression in a dose-dependent manner. IAP and Line1 quantitative RT-PCRs were run and parental MSC of each 5-azacytidine concentration were used to normalize the rest of the samples at that concentration. Error bars represent standard error. All experiments were performed in triplicate.</p
