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. Here, PIWIL1 is linked to neoplasm.