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.
Highlights
In all model systems examined, Piwi family members are expressed in stem cells, including germ and hematopoietic, and are essential for germ line and/or somatic stem cell self-renewal [1,2,3,4]
Following previous PCR-based observations that Hiwi is expressed in sarcomas [15] and that its expression correlates with prognosis [15], we examined Hiwi protein levels via immunohistochemistry (IHC) in a large primary human sarcoma tissue microarray (TMA) composed of numerous soft-tissue sarcomas
Using primary mesenchymal stem cells, transgenic mouse models and human tumor samples we show here that: (1) Hiwi is directly tumorigenic; (2) Hiwi-expressing tumors may be addicted to Hiwi expression; (3) Hiwi mediated tumorigenesis is associated with global DNA-hypermethylation and is reversible using DNA-methyltransferase inhibitors; (4) Hiwi associated global DNA-hypermethylation occurs at non-promoter CpG regions; and (5) Hiwi levels correlate inversely with levels of known tumor suppressor genes
Summary
In all model systems examined, Piwi family members are expressed in stem cells, including germ and hematopoietic, and are essential for germ line and/or somatic stem cell self-renewal [1,2,3,4]. Based on the data that implicate Piwi in transposon silencing, maintenance of genome integrity and exclusively embryonic and/ or stem cells expression, it is surprising that a growing body of studies reveal that Hiwi, the human ortholog of Piwi, is expressed in a diverse group of cancers including: seminomas [11], pancreatic [12] and gastric [13] adenocarcinomas, squamous cell carcinomas [14]; and sarcomas [15]. In sarcomas [15] and pancreatic [12] cancers higher Hiwi mRNA levels were predictive of worse clinical outcomes These data lead to an obvious conundrum: why would a gene that is critical for maintaining genome integrity during development be highly expressed in cancer? These data lead to an obvious conundrum: why would a gene that is critical for maintaining genome integrity during development be highly expressed in cancer? Since the above studies focused exclusively on Hiwi expression levels in cancer cells, mechanistic insight into Hiwi’s role in tumorigenesis remains completely unexamined
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