Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDA9MY0)

DOT Name	Piwi-like protein 4 (PIWIL4)
Gene Name	PIWIL4
Related Disease	Cervical cancer ( ) Cervical carcinoma ( ) Nervous system disease ( ) Adult germ cell tumor ( ) Alzheimer disease ( ) Attention deficit hyperactivity disorder ( ) Azoospermia ( ) Chromosomal disorder ( ) Colon cancer ( ) Colon carcinoma ( ) Epithelial ovarian cancer ( ) Gastric cancer ( ) Germ cell tumor ( ) Glioma ( ) Head and neck cancer ( ) Head and neck carcinoma ( ) Head-neck squamous cell carcinoma ( ) Hepatocellular carcinoma ( ) Lung squamous cell carcinoma ( ) Male infertility ( ) Metastatic malignant neoplasm ( ) Neoplasm ( ) Neuroblastoma ( ) Non-small-cell lung cancer ( ) Obesity ( ) Oligospermia ( ) Proliferative diabetic retinopathy ( ) Retinoblastoma ( ) Retinopathy ( ) Rheumatoid arthritis ( ) Schizophrenia ( ) Stomach cancer ( ) Testicular germ cell tumor ( ) Type-1/2 diabetes ( ) X-linked reticulate pigmentary disorder ( ) Colorectal carcinoma ( ) Pulmonary tuberculosis ( ) Werner syndrome ( ) Adult glioblastoma ( ) Clear cell renal carcinoma ( ) Colorectal adenocarcinoma ( ) Cryptorchidism ( ) Glioblastoma multiforme ( ) Lung cancer ( ) Lung carcinoma ( ) Non-insulin dependent diabetes ( ) Pneumonia ( ) Seminoma ( ) Triple negative breast cancer ( )
UniProt ID	PIWL4_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF02170 ; PF02171
Sequence	MSGRARVKARGIARSPSATEVGRIQASPLPRSVDLSNNEASSSNGFLGTSRISTNDKYGI SSGDAGSTFMERGVKNKQDFMDLSICTREKLAHVRNCKTGSSGIPVKLVTNLFNLDFPQD WQLYQYHVTYIPDLASRRLRIALLYSHSELSNKAKAFDGAILFLSQKLEEKVTELSSETQ RGETIKMTITLKRELPSSSPVCIQVFNIIFRKILKKLSMYQIGRNFYNPSEPMEIPQHKL SLWPGFAISVSYFERKLLFSADVSYKVLRNETVLEFMTALCQRTGLSCFTQTCEKQLIGL IVLTRYNNRTYSIDDIDWSVKPTHTFQKRDGTEITYVDYYKQQYDITVSDLNQPMLVSLL KKKRNDNSEAQLAHLIPELCFLTGLTDQATSDFQLMKAVAEKTRLSPSGRQQRLARLVDN IQRNTNARFELETWGLHFGSQISLTGRIVPSEKILMQDHICQPVSAADWSKDIRTCKILN AQSLNTWLILCSDRTEYVAESFLNCLRRVAGSMGFNVDYPKIIKVQENPAAFVRAIQQYV DPDVQLVMCILPSNQKTYYDSIKKYLSSDCPVPSQCVLARTLNKQGMMMSIATKIAMQMT CKLGGELWAVEIPLKSLMVVGIDVCKDALSKDVMVVGCVASVNPRITRWFSRCILQRTMT DVADCLKVFMTGALNKWYKYNHDLPARIIVYRAGVGDGQLKTLIEYEVPQLLSSVAESSS NTSSRLSVIVVRKKCMPRFFTEMNRTVQNPPLGTVVDSEATRNEWYDFYLISQVACRGTV SPTYYNVIYDDNGLKPDHMQRLTFKLCHLYYNWPGIVSVPAPCQYAHKLTFLVAQSIHKE PSLELANHLFYL
Function	Plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Directly binds piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. Associates with secondary piRNAs antisense and PIWIL2/MILI is required for such association. The piRNA process acts upstream of known mediators of DNA methylation. Does not show endonuclease activity. Plays a key role in the piRNA amplification loop, also named ping-pong amplification cycle, by acting as a 'slicer-incompetent' component that loads cleaved piRNAs from the 'slicer-competent' component PIWIL2 and target them on genomic transposon loci in the nucleus. May be involved in the chromatin-modifying pathway by inducing 'Lys-9' methylation of histone H3 at some loci. In addition to its role in germline, PIWIL4 also plays a role in the regulation of somatic cells activities. Plays a role in pancreatic beta cell function and insulin secretion. Involved in maintaining cell morphology and functional integrity of retinal epithelial through Akt/GSK3alpha/beta signaling pathway. When overexpressed, acts as an oncogene by inhibition of apoptosis and promotion of cells proliferation in tumors.
Tissue Specificity	Ubiquitously expressed . Detected in retina, retinal pigment epithelia cells (RPE) (at protein level) .
Reactome Pathway	PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884 )

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Cervical cancer	DISFSHPF	Definitive	Biomarker	[1]
Cervical carcinoma	DIST4S00	Definitive	Biomarker	[1]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[2]
Adult germ cell tumor	DISJUCQ7	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[5]
Azoospermia	DIS94181	Strong	Altered Expression	[6]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Germ cell tumor	DIS62070	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Head and neck cancer	DISBPSQZ	Strong	Altered Expression	[12]
Head and neck carcinoma	DISOU1DS	Strong	Altered Expression	[12]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[14]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[15]
Male infertility	DISY3YZZ	Strong	Altered Expression	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Altered Expression	[17]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[19]
Obesity	DIS47Y1K	Strong	Posttranslational Modification	[20]
Oligospermia	DIS6YJF3	Strong	Biomarker	[21]
Proliferative diabetic retinopathy	DISQZ13G	Strong	Biomarker	[22]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[23]
Retinopathy	DISB4B0F	Strong	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[24]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[25]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[22]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Altered Expression	[22]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[26]
Pulmonary tuberculosis	DIS6FLUM	moderate	Biomarker	[27]
Werner syndrome	DISZY45W	moderate	Biomarker	[28]
Adult glioblastoma	DISVP4LU	Limited	Genetic Variation	[29]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[30]
Colorectal adenocarcinoma	DISPQOUB	Limited	Biomarker	[31]
Cryptorchidism	DISYUD2P	Limited	Altered Expression	[32]
Glioblastoma multiforme	DISK8246	Limited	Genetic Variation	[29]
Lung cancer	DISCM4YA	Limited	Biomarker	[33]
Lung carcinoma	DISTR26C	Limited	Biomarker	[33]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[34]
Pneumonia	DIS8EF3M	Limited	Altered Expression	[35]
Seminoma	DIS3J8LJ	Limited	Altered Expression	[36]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[37]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Piwi-like protein 4 (PIWIL4).	[38]
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3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Piwi-like protein 4 (PIWIL4).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Piwi-like protein 4 (PIWIL4).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Piwi-like protein 4 (PIWIL4).	[41]
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References

1	PIWIL4 regulates cervical cancer cell line growth and is involved in down-regulating the expression of p14ARF and p53.FEBS Lett. 2012 May 7;586(9):1356-62. doi: 10.1016/j.febslet.2012.03.053. Epub 2012 Mar 31.
2	PIWI Proteins and piRNAs in the Nervous System.Mol Cells. 2019 Dec 31;42(12):828-835. doi: 10.14348/molcells.2019.0241.
3	Differential Regulation of PIWI-LIKE 2 Expression in Primordial Germ Cell Tumor Cell Lines by Promoter Methylation.Front Genet. 2018 Sep 20;9:375. doi: 10.3389/fgene.2018.00375. eCollection 2018.
4	Single nucleotide polymorphisms in piRNA-pathway genes: an insight into genetic determinants of human diseases.Mol Genet Genomics. 2020 Jan;295(1):1-12. doi: 10.1007/s00438-019-01612-5. Epub 2019 Oct 14.
5	Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan.Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1359-68. doi: 10.1002/ajmg.b.30860.
6	Altered PIWI-LIKE 1 and PIWI-LIKE 2 mRNA expression in ejaculated spermatozoa of men with impaired sperm characteristics.Asian J Androl. 2018 May-Jun;20(3):260-264. doi: 10.4103/aja.aja_58_17.
7	Smoking status regulates a novel panel of PIWI-interacting RNAs in head and neck squamous cell carcinoma.Oral Oncol. 2017 Feb;65:68-75. doi: 10.1016/j.oraloncology.2016.12.022. Epub 2016 Dec 31.
8	Circulating PIWI-Interacting RNAs piR-5937 and piR-28876 Are Promising Diagnostic Biomarkers of Colon Cancer.Cancer Epidemiol Biomarkers Prev. 2018 Sep;27(9):1019-1028. doi: 10.1158/1055-9965.EPI-18-0318. Epub 2018 Jul 5.
9	Genome-wide profiling of the PIWI-interacting RNA-mRNA regulatory networks in epithelial ovarian cancers.PLoS One. 2018 Jan 10;13(1):e0190485. doi: 10.1371/journal.pone.0190485. eCollection 2018.
10	An atlas of gastric PIWI-interacting RNA transcriptomes and their utility for identifying signatures of gastric cancer recurrence.Gastric Cancer. 2016 Apr;19(2):660-665. doi: 10.1007/s10120-015-0487-y. Epub 2015 Mar 17.
11	Mechanism of piR-DQ590027/MIR17HG regulating the permeability of glioma conditioned normal BBB.J Exp Clin Cancer Res. 2018 Oct 11;37(1):246. doi: 10.1186/s13046-018-0886-0.
12	HPV status is associated with altered PIWI-interacting RNA expression pattern in head and neck cancer.Oral Oncol. 2016 Apr;55:43-48. doi: 10.1016/j.oraloncology.2016.01.012. Epub 2016 Feb 4.
13	Identification and characterization of dysregulated P-element induced wimpy testis-interacting RNAs in head and neck squamous cell carcinoma.Oncol Lett. 2019 Mar;17(3):2615-2622. doi: 10.3892/ol.2019.9913. Epub 2019 Jan 9.
14	Hiwi overexpression does not affect proliferation, migration or apoptosis of liver cancer cells in vitro or in vivo.Oncol Lett. 2018 Jun;15(6):9711-9718. doi: 10.3892/ol.2018.8585. Epub 2018 Apr 26.
15	A piRNA-like Small RNA Induces Chemoresistance to Cisplatin-Based Therapy by Inhibiting Apoptosis in Lung Squamous Cell Carcinoma.Mol Ther Nucleic Acids. 2017 Mar 17;6:269-278. doi: 10.1016/j.omtn.2017.01.003. Epub 2017 Jan 24.
16	Overexpression of PIWI proteins in human stage III epithelial ovarian cancer with lymph node metastasis.Cancer Biomark. 2013;13(5):315-21. doi: 10.3233/CBM-130360.
17	PIWIL2 stabilizes -catenin to promote cell cycle and proliferation in tumor cells.Biochem Biophys Res Commun. 2019 Aug 27;516(3):819-824. doi: 10.1016/j.bbrc.2019.06.136. Epub 2019 Jun 28.
18	PIWI-interacting RNA 39980 promotes tumor progression and reduces drug sensitivity in neuroblastoma cells.J Cell Physiol. 2020 Mar;235(3):2286-2299. doi: 10.1002/jcp.29136. Epub 2019 Sep 3.
19	The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer.Oncotarget. 2015 Oct 13;6(31):31544-56. doi: 10.18632/oncotarget.3003.
20	Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood.Epigenetics. 2015;10(11):995-1005. doi: 10.1080/15592294.2015.1080411.
21	Genetic variants in Piwi-interacting RNA pathway genes confer susceptibility to spermatogenic failure in a Chinese population.Hum Reprod. 2010 Dec;25(12):2955-61. doi: 10.1093/humrep/deq274. Epub 2010 Oct 11.
22	PIWI-like protein, HIWI2: A novel player in proliferative diabetic retinopathy.Exp Eye Res. 2018 Dec;177:191-196. doi: 10.1016/j.exer.2018.08.018. Epub 2018 Aug 23.
23	PIWI-like protein, HIWI2 is aberrantly expressed in retinoblastoma cells and affects cell-cycle potentially through OTX2.Cell Mol Biol Lett. 2017 Aug 29;22:17. doi: 10.1186/s11658-017-0048-y. eCollection 2017.
24	Expression and Regulation of PIWIL-Proteins and PIWI-Interacting RNAs in Rheumatoid Arthritis.PLoS One. 2016 Nov 28;11(11):e0166920. doi: 10.1371/journal.pone.0166920. eCollection 2016.
25	Profiling of the small RNA populations in human testicular germ cell tumors shows global loss of piRNAs.Mol Cancer. 2015 Aug 12;14:153. doi: 10.1186/s12943-015-0411-4.
26	Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer.Mol Cancer. 2018 Jan 30;17(1):16. doi: 10.1186/s12943-018-0767-3.
27	Specific PIWI-interacting small noncoding RNA expression patterns in pulmonary tuberculosis patients.Epigenomics. 2019 Dec;11(16):1779-1794. doi: 10.2217/epi-2018-0142. Epub 2019 Nov 22.
28	Roles of RNase P and Its Subunits.Trends Genet. 2017 Sep;33(9):594-603. doi: 10.1016/j.tig.2017.06.006. Epub 2017 Jul 8.
29	MiRNA-154-5p inhibits cell proliferation and metastasis by targeting PIWIL1 in glioblastoma.Brain Res. 2017 Dec 1;1676:69-76. doi: 10.1016/j.brainres.2017.08.014. Epub 2017 Aug 24.
30	Mitochondrial PIWI-interacting RNAs are novel biomarkers for clear cell renal cell carcinoma.World J Urol. 2019 Aug;37(8):1639-1647. doi: 10.1007/s00345-018-2575-1. Epub 2018 Nov 28.
31	PIWI-interacting RNA-54265 is oncogenic and a potential therapeutic target in colorectal adenocarcinoma.Theranostics. 2018 Oct 6;8(19):5213-5230. doi: 10.7150/thno.28001. eCollection 2018.
32	Piwi-pathway alteration induces LINE-1 transposon derepression and infertility development in cryptorchidism.Sex Dev. 2015;9(2):98-104. doi: 10.1159/000375351. Epub 2015 Mar 13.
33	Identification and characterization of RASSF1C piRNA target genes in lung cancer cells.Oncotarget. 2017 May 23;8(21):34268-34282. doi: 10.18632/oncotarget.15965.
34	PIWI-interacting RNAs as novel regulators of pancreatic beta cell function.Diabetologia. 2017 Oct;60(10):1977-1986. doi: 10.1007/s00125-017-4368-2. Epub 2017 Jul 16.
35	Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells.J Clin Invest. 2017 Oct 2;127(10):3866-3876. doi: 10.1172/JCI94639. Epub 2017 Sep 18.
36	Distinguishing epigenetic features of preneoplastic testis tissues adjacent to seminomas and nonseminomas.Oncotarget. 2016 Apr 19;7(16):22439-47. doi: 10.18632/oncotarget.7074.
37	Circulating noncoding RNAbiomarker potential in neoadjuvant chemotherapy of triple negative breast cancer?.Int J Oncol. 2020 Jan;56(1):47-68. doi: 10.3892/ijo.2019.4920. Epub 2019 Nov 25.
38	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
39	Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
40	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
41	Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.