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.

Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer

“…Ts-3676 methylation state and possibly provide sequence specificity for DNA methylation (14,15). Because of the similarity of tsRNAs to piRNAs, we hypothesized and then proved that these molecules can interact with Piwi proteins (24).…”

“…Although miRNAs are created through a double-stranded precursor molecule (12), piRNAs biogenesis involves long single-stranded precursor molecules (11). PiRNAs interact with Piwi proteins and appear to cooperate with DNA methyltransferases to affect methylation of genes, suggesting that Piwi/piRNAs complexes are global regulators of chromatin state (14,15). A few years ago, a new class of small RNAs was reported to derive from tRNAs as a consequence of tRNA processing (16).…”

Hiwi Knockdown Inhibits the Growth of Lung Cancer in Nude Mice

“…Moreover, recent data suggested that Hiwi gene was required to maintain the stemness of hematopoietic stem cells (Sharma et al, 2001). Thus it was proposed that Hiwi gene may be a key regulator in maintenance of cancer stem cell populations as well (Taubert et al, 2007;Siddiqi et al, 2012).…”

Silencing HIWI suppresses the growth, invasion and migration of glioma cells

“…Therefore, it is not surprising that HiWi has been implicated in oncogenesis. Several studies have demonstrated that HiWi is expressed in tumor tissues, and is one of the most important elements in the regulation of cancer cells (8,9). HIWI was also correlated with patient prognosis in pancreatic, colon, colorectal, lung, and endometrial cancer (10)(11)(12)(13)(14).…”