title: Hiwi mediated tumorigenesis is associated with DNA hypermethylation.
abstract: Expression 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.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Siddiqi
authors.forename: Melissa
authors.initials: M
authors.lastname: Terry
authors.forename: Igor
authors.initials: I
authors.lastname: Matushansky
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics* / Q000502:physiology*; D001483:Base Sequence; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D040081:Protein Array Analysis; D012509:Sarcoma / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D012513:Sarcoma, Experimental / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D014410:Tumor Stem Cell Assay
chemical_list: D060565:Argonaute Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C421088:PIWIL1 protein, human