Abstract
Germ line-specific genes are activated in somatic cells during tumorigenesis, and are accordingly referred to as cancer germline genes. Such genes that act on piRNA (Piwi-interacting RNA) processing play an important role in the progression of cancer cells. Here, we show that the spermatogenic transposon silencer maelstrom (Mael), a piRNA-processing factor, is required for malignant transformation and survival of cancer cells. A specific Mael isoform was distinctively overexpressed in diverse human cancer cell lines and its depletion resulted in cancer-specific cell death, characterized by apoptosis and senescence, accompanied by an increase in reactive oxygen-species and DNA damage. These biochemical changes and death phenotypes induced by Mael depletion were dependent on ATM. Interestingly Mael was essential for Myc/Ras-induced transformation, and its overexpression inhibited Ras-induced senescence. In addition, Mael repressed retrotransposon activity in cancer cells. These results suggest that Mael depletion induces ATM-dependent DNA damage, consequently leading to cell death specifically in cancer cells. Moreover, Mael possesses oncogenic potential that can protect against genetic instability.
Highlights
Members of the Piwi protein family, which form ribonucleoprotein complexes that process Piwi-associated RNAs, function to silence retrotransposons and other repeat elements during spermatogenesis by degrading transcripts or regulating epigenetic modulation of chromatin, thereby maintaining genetic stability [1,2,3]
To explore the role of Mael in tumor cells, we examined the phenotype of tumor cells following siRNAmediated depletion of Mael
Proliferation was significantly reduced by Mael depletion in all tested cancer cells (HeLa, Hep3B, and MDA-MB-231), while there was no difference in normal cells (BJ, WI-38, and IMR90) (Figure 1C)
Summary
Members of the Piwi protein family, which form ribonucleoprotein complexes that process Piwi-associated RNAs (piRNAs), function to silence retrotransposons and other repeat elements during spermatogenesis by degrading transcripts or regulating epigenetic modulation of chromatin, thereby maintaining genetic stability [1,2,3]. Some Piwi subfamily members are overexpressed in various types of cancers and have been suggested to play a role during tumorigenesis. Inactivation of the several piRNA-processing factors suppresses malignant growth in Drosophila [6], and orthologs of some of these genes that plays a role in tumor development, are overexpressed in a variety of human somatic tumors [6,7,8,9]. The spermatogenic transposon silencer Mael (maelstrom) is a PIWI-interacting protein that localizes to both perinuclear nuage and nuclei [10,11,12,13]. It has been speculated that Mael may function at steps downstream of piRNA biogenesis, such as shuttling Piwi complexes from nuage to the nucleus [12, 14]
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