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The Emerging Role of the Pirna/Piwi Complex in Cancer

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The Emerging Role of the Pirna/Piwi Complex in Cancer Liu et al. Molecular Cancer (2019) 18:123 https://doi.org/10.1186/s12943-019-1052-9 REVIEW Open Access The emerging role of the piRNA/piwi complex in cancer Yongmei Liu1†, Mei Dou2†, Xuxia Song3, Yanhan Dong4, Si Liu1, Haoran Liu1, Jiaping Tao1, Wenjing Li1, Xunhua Yin1 and Wenhua Xu1* Abstract Piwi interacting RNAs (piRNAs) constitute novel small non-coding RNA molecules of approximately 24–31 nucleotides in length that often bind to members of the piwi protein family to play regulatory roles. Recently, emerging evidence suggests that in addition to the mammalian germline, piRNAs are also expressed in a tissue- specific manner in a variety of human tissues and modulate key signaling pathways at the transcriptional or post- transcriptional level. In addition, a growing number of studies have shown that piRNA and PIWI proteins, which are abnormally expressed in various cancers, may serve as novel biomarkers and therapeutic targets for tumor diagnostics and treatment. However, the functions of piRNAs in cancer and their underlying mechanisms remain incompletely understood. In this review, we discuss current findings regarding piRNA biogenetic processes, functions, and emerging roles in cancer, providing new insights regarding the potential applications of piRNAs and piwi proteins in cancer diagnosis and clinical treatment. Keywords: piRNA/piwi complex, Cancer, Function, Biomarker Background ome rearrangement, epigenetic regulation, protein PIWI-interacting RNAs (piRNAs) constitute a class of regulation, and germ stem-cell maintenance [4]. The recently discovered small non-coding RNAs in germ- piwi family exhibits highly conserved structure and and somatic cells comprising 24–31 nucleotides (nt) function across multiple organisms [5], including fruit with a 5′-terminal uridine or tenth position adenosine fly(PIWI,Aubergine,andAGO3proteins)[6], mouse bias, lacking clear secondary structure motifs [1]. (MILI, MIWI, and MIWI2) [7–11], human (HILI, They were first described in 2001 in Drosophila testes HIWI1, HIWI2 and HIWIL3) [6, 12–14], zebrafish as small RNAs derived from the Su(Ste) tandem re- (ZILI and ZIWI) [15], and nematode (PRG-1 and peats, which silence Stellate transcripts to maintain PRG-2) [16]. Moreover, aberrant piRNA or PIWI pro- male fertility [2]. Unlike miRNAs and siRNAs, which tein expression has recently been reported in some typically rely on RNase type III enzymes to convert human cancer, with some piRNAs/piwi complexes double-stranded RNA precursors into functional small participating in tumorigenesis and associated with RNAs, mature piRNAs derive from an initial cancer prognosis [17–19]. transcript encompassing a piRNA cluster via a unique Cancer accounts for 1.2 million deaths annually in biosynthesis process [3]. piRNAs can bind to piwi China, with an additional 1.6 million people diagnosed proteins to form a piRNA/piwi complex, thereby each year [20]. Treatments are often ineffective owing to influencing transposon silencing, spermiogenesis, gen- relatively late disease detection combined with high rates of metastasis and recurrence [21], highlighting the need for novel biomarkers of cancer diagnosis and prognosis along with new targets for effective therapeutic ap- proaches. Notably, numerous studies have implicated the * Correspondence: [email protected] †Yongmei Liu and Mei Dou contributed equally to this work. piRNAs/piwi complex in the occurrence, development, 1Department of Inspection, The medical faculty of Qingdao University, Qingdao 266003, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. Molecular Cancer (2019) 18:123 Page 2 of 15 metastasis, and recurrence of e.g., breast (BC) [22], lung coding genes to initiate transcription and are not equiva- (LC) cancer [17]. The present review summarizes the lat- lently processed [3, 23]. (Fig. 1). est research regarding piRNAs including their biosyn- thesis, functions, and mechanism, along with their roles in different cancers and as potential biomarkers. Two major pathways generate piRNAs piRNA clusters produce primary piRNAs that are transported to the cytoplasmic Yb body [24, 25]. piRNA biosynthesis mechanism Zucchini (Zuc) and its co-factor Minotaur (Mino) in- Transcription of piRNA clusters cise primary piRNAs, producing piRNA intermediates A large fraction of piRNAs that can be uniquely mapped with a 5′ uracil [26, 27]. Piwi protein contains an originate from two types of extended (up to 200 kb) gen- evolutionarily conserved structure consisting of a PAZ omic loci, termed piRNA clusters [23]. Similar to coding and piwi domain. PAZ preferentially binds piRNA in- genes, uni-stranded clusters contain promoters marked by termediates with 5′ uracil, as observed for silkworm Pol II Ser5P and H3K4me2 peaks that produce transcripts piwi in vitro [28]. Upon binding to piwi protein, piR- via RNA polymerase II, which undergo5-terminal capping, NAs mature through 3′-end cleavage by the Zuc 3-terminal polyadenylation, and sometimes selective spli- riboendonuclease [29], or via the Papi-dependent cing. Conversely, dual-strand clusters are transcribed from trimmer. Subsequent methylation by Hen1 yields the both genomic strands, depend on promoters of nearby mature piRNA-piwi complex [3, 30](Fig.1). Fig. 1 piRNA biosynthesis mechanism. Within the nucleus, two types of piRNA clusters are transcribed to produce the primary piRNAs, Zuc and its co-factors incised primary piRNAs producing piRNA intermediates with a 5′ uracil in Yb body. piRNA intermediates linked piwi that are cleavage by Zuc or Papi-dependent trimmer to form 3’end . Following methylation in cytoplasm, the mature piRNA-piwi complex is producted. Abbreviations: TSS: transcription start site; Zuc: zucchini Liu et al. Molecular Cancer (2019) 18:123 Page 3 of 15 piRNA/piwi protein function and mechanism in cancer natural killer cells [34]. piR-021285 overexpression facili- Recent studies indicate that piRNAs play a vital role tated ARHGAP11A methylation at a CpG site within the 5′ in physiological and pathological processes at the UTR/first exon, decreasing mRNA (pro-apoptosis) expres- transcriptional or post-transcriptional level. Here, we sion and inhibiting BC cell apoptosis [35]. In multiple mye- summarize the function and mechanisms of piRNAs loma (MM), piRNA-823 directly recruited de novo DNA in cancer (Fig. 2). methyltransferases DNMT3A and DNMT3B in primary CD138+ MM cells, increasing global DNA methylation and piRNAs/piwi complex-mediated transcriptional gene inhibiting tumor suppressor p16INK4A expression [36]. silencing (TGS) piRNA/piwi complexes enter the nucleus and bind its gen- piRNAs/piwi complex- mediated post-transcriptional gene omic target through a nascent transcript by sequence com- silencing (PTGS) plementary. Once combined with Panoramix (Panx), the Numerous studies have found that many piRNAs piRNA-proteins complex induces TGS by recruiting silen- regulate post-transcriptional networks to inhibit target cing machinery components. Eggless (Egg) and its co-factor function through piRNA-RNA interactions, similar to Windei (Wde) add repressive histone 3 lysine 9 trimethyla- miRNA mechanisms. These RNAs include mRNA tion (H3K9me3) marks to the target DNA; subsequently, [37], transcribed pseudogenes [22], and long noncod- heterochromatin protein 1 (HP1) is recruited, causing ing RNA (lncRNA) [38]. Effective mRNA: piRNA heterochromatin formation. Lysine-specificdemethylase1 interaction requires strict base pairing within 2–11 nt (Lsd1) removes activating H3K4me2 marks from promoter at the 5′-end of piRNA and less stringent base regions, inhibiting RNA Pol II transcription [31]. piRNA/ pairing within 12–21 nt [39](Fig.2b). Functional piwi complex also recruits DNA methyltransferase piRNA-induced silencing complexes (pi-RISCs), com- (DNMT) to methylate genic CpG sites (non-transposable prised of MIWI, piRNAs, and CAF1 deadenylase in element (TE) protein-coding), altering transcriptional activ- mouse elongating spermatids, mediate mRNA deade- ity [32](Fig. 2a). In Aplysia neurons, an endogenously nylation and decay via an miRNA-like mechanism expressed piRNA induced CREB2 promoter methylation with guider piRNAs and CAF1. The resulting elimin- [33]. Furthermore, expression of a “piRNA-like” 28-nt ation of large mRNA quantities may promote nucleus transcript antisense to the KIR3DL1 promoter strongly condensation and cytoplasm exclusion to complete correlated with KIR3DL1 promoter methylation in CD56+ spermatozoa formation in mammals [40]. piRNA-piwi Fig. 2 piRNA/piwi protein function. a. At TGS level, the piRNA-proteins complex recruit silencing machinery components to bring repressive H3K9me3 marks to target DNA body and remove active H3K4me2 marks from promoter regions. In addition, piRNAs/piwi complex recruits DNMT, results in methylation at CpG sites in genic. b. At PTGS level, the piRNAs/piwi complex bind to targeted RNAs and impede their function by
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