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. 2020 Oct 5;8(5):603–622. doi: 10.1016/j.gendis.2020.09.006

Figure 4.

Fig. 4

Mechanism of piRNAs in cancer. (A) TGS or TGA by piRNAs via aberrant DNA methylation: In cancer, the piRNA–PIWI complex represses tumor-suppressor genes (TSGs) via recruiting DNA methyltransferases to the promoter and activates oncogenes by recruiting TET to the gene body. piRNA variants fail to bind to target regions and to form a piRNA–PIWI–DNMT complex, resulting in gene body hypomethylation and oncogene activation. (B) TGS or TGA by piRNAs via histone modification: the piRNA–PIWI complex induces the transformation between heterochromatin (condensed) and euchromatin (open) by recruiting methyltransferases or demethylases to histones and depositing active (H3K4me3) or repressive histone markers (H3K9me3 or H3K27me3). (C) PTGS by piRNAs via mRNA decay or deregulation: the piRNA–PIWI complex recruits the TRAMP complex and leads to mRNA decay. The piRNA–PIWI complex results in mRNA degradation via the slicer activity of PIWI. Whether or not other factors are needed is unknown. (D) PTGS or PTGA by piRNAs via protein modification: piRNA loading induces a conformational change in PIWI and enhances its interaction with proteasomes, resulting in protein phosphorylation or ubiquitination. Abbreviation: CDS, coding DNA sequence; DNMT, DNA methyltransferase; H3K9, H3 lysine 9; H3K27, H3 lysine 27; H3K4, H3 lysine 4; KDM, lysine demethylase 6A; PTGS, post-transcriptional gene silencing; PTGA, post-transcriptional gene activation; TF, transcription factor; SUV39H1, suppressor of variegation 3–9 homolog 1; TET, tet methylcytosine dioxygenase 1; TGA, transcriptional gene activation; TGS, transcriptional gene silencing; UTR, untranslated region.