Special Issue for Advanced Immunochemical Studies

Function and mechanism of PIWI/piRNA in cancer

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  • ① Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; ② Yale Stem Cell Center and Department of Cell Biology, School of Medicine, Yale University, New Haven, CT 06510, USA

Received date: 2021-06-16

  Online published: 2021-10-22

Abstract

PIWI proteins, a subfamily of PAZ/PIWI domain (PPD) family RNA-binding proteins, are best known for their functions in silencing transposons and germline development by partnering with small noncoding RNA called PIWI-interacting RNA (piRNA). In addition to its prominent role in the germline, PIWI proteins are gaining increasing interests for cancer research because they are usually hardly expressed in somatic tissues but gain abnormal expression in cancer cells, making them promising targets for precision therapy. In this review, we first provide an overview on how PIWI proteins, together with piRNAs, multifacetedly regulate the expression of major classes of RNA in germ cells. Then, we summarize the expression and function of PIWI proteins and piRNAs in different types of cancer and consider the limitations and possible misunderstanding of PIWI and piRNA in cancer research. In addition, we discuss the recently discovered piRNA-independent functions and regulatory mechanisms of PIWI in cancer cells that have the traditional concept.

Key words:  ; PIWI, piRNA, cancer 

Cite this article

SHI Shuo, WANG Chen, LIN Haifan . Function and mechanism of PIWI/piRNA in cancer[J]. Chinese Journal of Nature, 2021 , 43(5) : 313 -322 . DOI: 10.3969/j.issn.0253-9608.2021.05.001

References

[1] SONG J J, SMITH S K, HANNON G J, et al. Crystal structure of Argonaute and its implications for RISC slicer activity [J]. Science, 2004, 305(5689): 1434-1437. 

[2] MATSUMOTO N, NISHIMASU H, SAKAKIBARA K, et al. Crystal structure of silkworm PIWI-clade Argonaute Siwi bound to piRNA [J]. Cell, 2016, 167(2): 484-497. 

[3] WANG C, LIN H. Roles of piRNAs in transposon and pseudogene regulation of germline mRNAs and lncRNAs [J]. Genome Biol, 2021, 22(1): 27. 

[4] GUNAWARDANE L S, KUNIAKI S, KAZUMICHI M N, et al. A slicer-mediated mechanism for repeat-associated siRNA 5' end formation in Drosophila [J]. Science, 2007, 315(5818): 1587-1590. 

[5] OKAMURA K, ISHIZUKA A, SIOMI H, et al. Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways [J]. Genes Dev, 2004, 18(14): 1655-1666. 

[6] VAGIN V V, SIGOVA A, LI C, et al. A distinct small RNA pathway silences selfish genetic elements in the germline [J]. Science, 2006, 313(5785): 320-324. 

[7] KIM V N, HAN J, SIOMI M C. Biogenesis of small RNAs in animals [J]. Nat Rev Mol Cell Biol, 2009, 10(2): 126-139. 

[8] TEIXEIRA F K, OKUNIEWSKA M, MALONE C D, et al. piRNAmediated regulation of transposon alternative splicing in the soma and germ line [J]. Nature, 2017, 552(7684): 268-272. 

[9] LEWIS S H, QUARLES K A, YANG Y, et al. Pan-arthropod analysis reveals somatic piRNAs as an ancestral defence against transposable elements [J]. Nat Ecol Evol, 2018, 2(1): 174-181. 

[10] ROSS R J, WEINER M M, LIN H. PIWI proteins and PIWIinteracting RNAs in the soma [J]. Nature, 2014, 505(7483): 353-359.

[11] ARAVIN A, GAIDATZIS D, PFEFFER S, et al. A novel class of small RNAs bind to MILI protein in mouse testes [J]. Nature, 2006, 442(7099): 203-207. 

[12] GIRARD A, SACHIDANANDAM R, HANNON G J, et al. A germline-specific class of small RNAs binds mammalian Piwi proteins [J]. Nature, 2006, 442(7099): 199-202. 

[13] GRIVNA S T, BEYRET E, WANG Z, et al. A novel class of small RNAs in mouse spermatogenic cells [J]. Genes Dev, 2006 20(13): 1709-1714. 

[14] LAU N C, SETO A G, KIM J, et al. Characterization of the piRNA complex from rat testes [J]. Science, 2006, 313(5785): 363-367. 

[15] GU W, LEE H C, CHAVES D, et al. CapSeq and CIP-TAP identify Pol II start sites and reveal capped small RNAs as C. elegans piRNA precursors [J]. Cell, 2012, 151(7): 1488-1500. 

[16] RUBY J G, JAN C, PLAYER C, et al. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans [J]. Cell, 2006, 127(6): 1193-1207. 

[17] BRENNECKE J, ARAVIN A A, STARK A, et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila [J]. Cell, 2007, 128(6): 1089-1103. 

[18] SAXE J P, CHEN M, ZHAO H, et al. Tdrkh is essential for spermatogenesis and participates in primary piRNA biogenesis in the germline [J]. EMBO J, 2013, 32(13): 1869-1885. 

[19] KAWAOKA S, IZUMI N, KATSUMA S, et al. 3' end formation of PIWI-interacting RNAs in vitro [J]. Mol Cell, 2011, 43(6):1015- 1022. 

[20] TANG W, TU S, LEE H C, et al. The RNase PARN-1 trims piRNA 3'ends to promote transcriptome surveillance in C. elegans [J]. Cell, 2016, 164(5): 974-984. 

[21] IZUMI N, SHOJI K, SAKAGUCHI Y, et al. Identification and functional analysis of the pre-piRNA 3' trimmer in silkworms [J]. Cell, 2016, 164(5): 962-973. 

[22] HOMOLKA D, PANDEY R R, GORIAUX C, et al. PIWI slicing and RNA elements in precursors instruct directional primary piRNA biogenesis [J]. Cell Rep, 2015, 12(3): 418-428. 

[23] MOHN F, HANDLER D, BRENNECKE J. Noncoding RNA. piRNA-guided slicing specifies transcripts for Zucchini-dependent, phased piRNA biogenesis [J]. Science, 2015, 348(6236): 812-817. 

[24] HAN B W, WANG W, LI C, et al. Noncoding RNA. piRNA-guided transposon cleavage initiates Zucchini-dependent, phased piRNA production [J]. Science, 2015, 348(6236): 817-821. 

[25] HORWICH M D, LI C, MATRANGA C, et al. The Drosophila RNA methyltransferase, DmHen1, modifies germline piRNAs and singlestranded siRNAs in RISC [J]. Curr Biol, 2007, 17(14): 1265-1272. 

[26] SAITO K, SAKAGUCHI Y, SUZUKI T, et al. Pimet, the Drosophila homolog of HEN1, mediates 2'-O-methylation of Piwi-interacting RNAs at their 3' ends [J]. Genes Dev, 2007, 21(13): 1603-1608. 

[27] OHARA T, SAKAGUCHI Y, SUZUKI T, et al. The 3' termini of mouse Piwi-interacting RNAs are 2'-O-methylated [J]. Nat Struct Mol Biol, 2007, 14(4): 349-350. 

[28] KIRINO Y, MOURELATOS Z. Mouse Piwi-interacting RNAs are 2'-O-methylated at their 3' termini [J]. Nat Struct Mol Biol, 2007, 14(4): 347-348. 

[29] GAINETDINOV I, SKVORTSOVA Y, KONDRATIEVA S, et al. Two modes of targeting transposable elements by piRNA pathway in human testis [J]. RNA, 2017, 23(11): 1614-1625. 

[30] ZHANG F, WANG J, XU J, et al. UAP56 couples piRNA clusters to the perinuclear transposon silencing machinery [J]. Cell, 2012, 151(4): 871-884. 

[31] DE FAZIO S, BARTONICEK N, DI GIACOMOM, et al. The endonuclease activity of Mili fuels piRNA amplification that silences LINE1 elements [J]. Nature, 2011, 480(7376): 259-263. 

[32] DARRICARRERE N, LIU N, WATANABE T, et al. Function of Piwi, a nuclear Piwi/Argonaute protein, is independent of its slicer activity [J]. Proc Natl Acad Sci USA, 2013, 110(4): 1297-1302. 

[33] FAULKNER G J, KIMURA Y, DAUB C O, et al. The regulated retrotransposon transcriptome of mammalian cells [J]. Nat Genet, 2009, 41(5): 563-571. 

[34] WATANABE T, CHENG E C, ZHONG M, et al. Retrotransposons and pseudogenes regulate mRNAs and lncRNAs via the piRNA pathway in the germline [J]. Genome Res, 2015, 25(3): 368-380. 

[35] VOUREKAS A, ALEXIOU P, VRETTOS N, et al. Sequencedependent but not sequence-specific piRNA adhesion traps mRNAs to the germ plasm [J]. Nature, 2016, 531(7594): 390-394. 

[36] GOU L T, DAI P, YANG J H, et al. Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis [J]. Cell Res, 2014, 24(6): 680-700. 

[37] SHEN E Z, CHEN H, OZTURK A R, et al. Identification of piRNA binding sites reveals the Argonaute regulatory landscape of the C. elegans germline [J]. Cell, 172(5): 937-951. 

[38] ZHANG D, TU S, STUBNA M, et al. The piRNA targeting rules and the resistance to piRNA silencing in endogenous genes [J]. Science, 2018, 359(6375): 587-592. 

[39] SHPIZ S, RYAZANSKY S, OLOVNIKOV I, et al. Euchromatic transposon insertions trigger production of novel Pi- and endosiRNAs at the target sites in the Drosophila germline [J]. PLoS Genet, 2014, 10(2): e1004138. 

[40] KLEIN J D, QU C, YANG X, et al. c-Fos repression by Piwi regulates Drosophila ovarian germline formation and tissue morphogenesis [J]. PLoS Genet, 2016, 12(9): e1006281. 

[41] BARCKMANN B, PIERSON S, DUFOURT J, et al. Aubergine iCLIP reveals piRNA-dependent decay of mRNAs involved in germ cell development in the early embryo [J]. Cell Rep, 2015, 12(7): 1205-1216. 

[42] ROUGET C, PAPIN C, BOUREUX A, et al. Maternal mRNA deadenylation and decay by the piRNA pathway in the early Drosophila embryo [J]. Nature, 2010, 467(7319): 1128-1132. 

[43] LIM A K, TAO L, KAI T. piRNAs mediate posttranscriptional retroelement silencing and localization to pi-bodies in the Drosophila germline [J]. J Cell Biol, 2009, 186(3): 333-342. 

[44] HARRIS A N, MACDONALD P M. Aubergine encodes a Drosophila polar granule component required for pole cell formation and related to eIF2C [J]. Development, 2001, 128(14): 2823-2832. 

[45] RAMAT A, GARCIA-SILVA M, JAHAN C, et al. The PIWI protein Aubergine recruits eIF3 to activate translation in the germ plasm [J]. Cell Res, 2020, 30(5): 421-435. 

[46] DAI P, WANG X, GOU L-T, et al. A translation-activating function of MIWI/piRNA during mouse spermiogenesis [J]. Cell, 2019, 179(7): 1566-1581. 

[47] UNHAVAITHAYA Y, HAO Y, BEYRET E, et al. MILI, a PIWIinteracting RNA-binding protein, is required for germ line stem cell self-renewal and appears to positively regulate translation [J]. J Biol Chem, 2009, 284(10): 6507-6519. 

[48] GRIVNA S T, PYHTILA B, LIN H. MIWI associates with translational machinery and PIWI-interacting RNAs (piRNAs) in regulating spermatogenesis [J]. Proc Natl Acad Sci USA, 2006, 103(36): 13415-13420. 

[49] DUFOURT J, BONTONOU G, CHARTIER A, et al. piRNAs and Aubergine cooperate with Wispy poly(A) polymerase to stabilize mRNAs in the germ plasm [J]. Nat Commun, 2017, 8(1): 1305. 

[50] HSIEH C L, XIA J, LIN H. MIWI prevents aneuploidy during meiosis by cleaving excess satellite RNA [J]. EMBO J, 2020, 39(16): e103614. [51] QIAO D, ZEEMAN A M, DENG W, et al. Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas [J]. Oncogene, 2002, 21(25): 3988-3999. 

[52] DONG P, XIONG Y, KONNO Y, et al. Critical roles of PIWIL1 in human tumors: expression, functions, mechanisms, and potential clinical implications [J]. Front Cell Dev Biol, 2021, 9: 656993. 

[53] LIU Y, DOU Y, SONG X, et al. The emerging role of the piRNA/ piwi complex in cancer [J]. Mol Cancer, 2019, 18(1): 123. 

[54] WANG Q E, HAN C, MILUM K, et al. Stem cell protein Piwil2 modulates chromatin modifications upon cisplatin treatment [J]. Mutat Res, 2011, 708(1/2): 59-68. 

[55] LEE J H, SCHÜTTE D, WULF G, et al. Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway [J]. Hum Mol Genet, 2006, 15(2): 201-211. 

[56] LI W, MARTINEZ-USEROS J, GARCIA-CARBONERO N, et al. The clinical significance of PIWIL3 and PIWIL4 expression in pancreatic cancer [J]. J Clin Med, 2020, 9(5): 1252. 

[57] WANG Z, LIU N, SHI S, et al. The role of PIWIL4, an Argonaute family protein, in breast cancer [J]. J Biol Chem, 2016, 291(20): 10646-10658. 

[58] SU C, REN Z, WANG F, et al. PIWIL4 regulates cervical cancer cell line growth and is involved in down-regulating the expression of p14ARF and p53 [J]. FEBS Lett, 2012, 586(9): 1356-1362. 

[59] ZENG G, ZHANG D, LIU X, et al. Co-expression of Piwil2/Piwil4 in nucleus indicates poor prognosis of hepatocellular carcinoma [J]. Oncotarget, 2017, 8(3): 4607-4617. 

[60] TAN L, MAI D, ZHANG B, et al. PIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA [J]. Mol Cancer, 2019, 18(1): 9. 

[61] SULEMAN M, CHEN A, MA H, et al. PIR promotes tumorigenesis of breast cancer by upregulating cell cycle activator E2F1 [J]. Cell Cycle, 2019, 18(21): 2914-2927. 

[62] ZHANG H, REN Y, XU H, et al. The expression of stem cell protein Piwil2 and piR-932 in breast cancer [J]. Surg Oncol, 2013, 22(4): 217-223. 

[63] FU A, JACOBS D I, HOFFMAN A E, et al. PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome [J]. Carcinogenesis, 2015, 36(10): 1094-1102. 

[64] REEVES M E, FIREK M, JLIEDI A, et al. Identification and characterization of RASSF1C piRNA target genes in lung cancer cells [J]. Oncotarget, 2017, 8(21): 34268-34282. 

[65] LI D, LUO Y, GAO Y, et al. piR-651 promotes tumor formation in non-small cell lung carcinoma through the upregulation of cyclin D1 and CDK4 [J]. Int J Mol Med, 2016, 38(3): 927-936. 

[66] YAO J, WANG Y W, FANG B B, et al. piR-651 and its function in 95-D lung cancer cells [J]. Biomed Rep, 2016, 4(5): 546-550. [67] PENG L, SONG L, LIU C, et al. piR-55490 inhibits the growth of lung carcinoma by suppressing mTOR signaling [J]. Tumour Biol, 2016, 37(2): 2749-2756. 

[68] LIU X, SUN Y, GUO J, et al. Expression of hiwi gene in human gastric cancer was associated with proliferation of cancer cells [J]. Int J Cancer, 2006, 118(8): 1922-1929. 

[69] CHENG J, GUO J M, XIAO B-X, et al. piRNA, the new non-coding RNA, is aberrantly expressed in human cancer cells [J]. Clin Chim Acta, 2011, 412(17/18): 1621-1625. 

[70] MARTINEZ V D, ENFIELD K S S, ROWBOTHAM D A, et al. An atlas of gastric PIWI-interacting RNA transcriptomes and their utility for identifying signatures of gastric cancer recurrence [J]. Gastric Cancer, 2016, 19(2): 660-665. 

[71] WENG W, LIU N, TOIYAMA Y, et al. Novel evidence for a PIWIinteracting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer [J]. Mol Cancer, 2018, 17(1): 16.

[72] YIN J, JIANG X Y, QI W, et al. piR-823 contributes to colorectal tumorigenesis by enhancing the transcriptional activity of HSF1 [J].  Cancer Sci, 2017, 108(9): 1746-1756. 

[73] MAI D, DING P, TAN L, et al. PIWI-interacting RNA-54265 is oncogenic and a potential therapeutic target in colorectal adenocarcinoma [J]. Theranostics, 2018, 8(19): 5213-5230. 

[74] YU Y, XIAO J, HANN S S. The emerging roles of PIWI-interacting RNA in human cancers [J]. Cancer Manag Res, 2019, 11: 5895- 5909. 

[75] TOSAR J P, ROVIRA C, CAYOTA A. Non-coding RNA fragments account for the majority of annotated piRNAs expressed in somatic non-gonadal tissues [J]. Commun Biol, 2018, 1: 2. 

[76] SUZUKI R, HONDA S, KIRINO Y. PIWI expression and function in cancer [J]. Front Genet, 2012, 3: 204. 

[77] LI F, YUAN P, RAO M, et al. piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/ cyclosome to drive pancreatic cancer metastasis [J]. Nat Cell Biol, 2020, 22(4): 425-438. 

[78] SHI S, YANG Z Z, LIU S, et al. PIWIL1 promotes gastric cancer via a piRNA-independent mechanism [J]. Proc Natl Acad Sci USA, 2020, 117(36): 22390-22401. 

[79] YAMAGUCHI S, OE A, NISHIDA K M, et al. Crystal structure of Drosophila Piwi [J]. Nat Commun, 2020, 11(1): 858. 

[80] HAYASHI R, SCHNABL J, HANDLER D, et al. Genetic and mechanistic diversity of piRNA 3'-end formation [J]. Nature, 2016, 539(7630): 588-592. 

[81] WANG H, MA Z, NIU K, et al. Antagonistic roles of Nibbler and Hen1 in modulating piRNA 3' ends in Drosophila [J]. Development, 2016, 143(3): 530-539. 

[82] SAITO K, INAGAKI S, MITUYAMA T, et al. A regulatory circuit for piwi by the large Maf gene traffic jam in Drosophila [J]. Nature, 2009, 461(7268): 1296-1299.

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