Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7CRGZ3)

DOT Name	Piwi-like protein 1 (PIWIL1)
Synonyms	EC 3.1.26.-
Gene Name	PIWIL1
Related Disease	Gastric neoplasm ( ) Nervous system disease ( ) Alzheimer disease ( ) Chromosomal disorder ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Dilated cardiomyopathy 1A ( ) Drug dependence ( ) Endometrial cancer ( ) Endometrial carcinoma ( ) Epithelial ovarian cancer ( ) Gastric cancer ( ) Germ cell tumor ( ) Glioma ( ) Head-neck squamous cell carcinoma ( ) Lung adenocarcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Lung squamous cell carcinoma ( ) Male infertility ( ) Metastatic malignant neoplasm ( ) Neoplasm ( ) Neuroblastoma ( ) Non-small-cell lung cancer ( ) Pancreatic adenocarcinoma ( ) Retinoblastoma ( ) Rheumatoid arthritis ( ) Sarcoma ( ) Schizophrenia ( ) Stomach cancer ( ) Substance abuse ( ) Substance dependence ( ) Type-1/2 diabetes ( ) Head and neck cancer ( ) Head and neck carcinoma ( ) Pancreatic cancer ( ) Pulmonary tuberculosis ( ) Adult glioblastoma ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Clear cell renal carcinoma ( ) Colorectal adenocarcinoma ( ) Glioblastoma multiforme ( ) Liver cancer ( ) Non-insulin dependent diabetes ( ) Seminoma ( ) Triple negative breast cancer ( )
UniProt ID	PIWL1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2L5C; 2L5D; 3O3I; 3O6E; 3O7V; 6PI7
EC Number	3.1.26.-
Pfam ID	PF08699 ; PF05831 ; PF02170 ; PF02171
Sequence	MTGRARARARGRARGQETAQLVGSTASQQPGYIQPRPQPPPAEGELFGRGRQRGTAGGTA KSQGLQISAGFQELSLAERGGRRRDFHDLGVNTRQNLDHVKESKTGSSGIIVRLSTNHFR LTSRPQWALYQYHIDYNPLMEARRLRSALLFQHEDLIGKCHAFDGTILFLPKRLQQKVTE VFSKTRNGEDVRITITLTNELPPTSPTCLQFYNIIFRRLLKIMNLQQIGRNYYNPNDPID IPSHRLVIWPGFTTSILQYENSIMLCTDVSHKVLRSETVLDFMFNFYHQTEEHKFQEQVS KELIGLVVLTKYNNKTYRVDDIDWDQNPKSTFKKADGSEVSFLEYYRKQYNQEITDLKQP VLVSQPKRRRGPGGTLPGPAMLIPELCYLTGLTDKMRNDFNVMKDLAVHTRLTPEQRQRE VGRLIDYIHKNDNVQRELRDWGLSFDSNLLSFSGRILQTEKIHQGGKTFDYNPQFADWSK ETRGAPLISVKPLDNWLLIYTRRNYEAANSLIQNLFKVTPAMGMQMRKAIMIEVDDRTEA YLRVLQQKVTADTQIVVCLLSSNRKDKYDAIKKYLCTDCPTPSQCVVARTLGKQQTVMAI ATKIALQMNCKMGGELWRVDIPLKLVMIVGIDCYHDMTAGRRSIAGFVASINEGMTRWFS RCIFQDRGQELVDGLKVCLQAALRAWNSCNEYMPSRIIVYRDGVGDGQLKTLVNYEVPQF LDCLKSIGRGYNPRLTVIVVKKRVNTRFFAQSGGRLQNPLPGTVIDVEVTRPEWYDFFIV SQAVRSGSVSPTHYNVIYDNSGLKPDHIQRLTYKLCHIYYNWPGVIRVPAPCQYAHKLAF LVGQSIHREPNLSLSNRLYYL
Function	Endoribonuclease that plays a central role in postnatal germ cells 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 methylated 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. Strongly prefers a uridine in the first position of their guide (g1U preference, also named 1U-bias). Not involved in the piRNA amplification loop, also named ping-pong amplification cycle. Acts as an endoribonuclease that cleaves transposon messenger RNAs. Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation. Probable component of some RISC complex, which mediates RNA cleavage and translational silencing. Also plays a role in the formation of chromatoid bodies and is required for some miRNAs stability. Required to sequester RNF8 in the cytoplasm until late spermatogenesis; RNF8 being released upon ubiquitination and degradation of PIWIL1; [Isoform 3]: May be a negative developmental regulator.
Tissue Specificity	Expressed in spermatocytes and spermatids. Also detected in prostate cancer (at protein level). Detected in most fetal and adult tissues. Expressed in testes, specifically in germline cells; detected in spermatocytes and spermatids during spermatogenesis. Increased expression in testicular tumors originating from embryonic germ cells with retention of germ cells phenotype. No expression in testicular tumors of somatic origin, such as Sertoli cell and Leydig cell tumors. Overexpressed in gastric cancer cells. Isoform 3: Ubiquitously expressed, and specifically in CD34(+) hematopoietic progenitor cells but not in more differentiated cells.
Reactome Pathway	PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884 )

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Gastric neoplasm	DISOKN4Y	Definitive	Biomarker	[1]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[7]
Drug dependence	DIS9IXRC	Strong	Biomarker	[8]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[10]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[11]
Germ cell tumor	DIS62070	Strong	Altered Expression	[12]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[14]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[17]
Male infertility	DISY3YZZ	Strong	Altered Expression	[18]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Altered Expression	[20]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[22]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[23]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[24]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[25]
Sarcoma	DISZDG3U	Strong	Altered Expression	[26]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[11]
Substance abuse	DIS327VW	Strong	Biomarker	[8]
Substance dependence	DISDRAAR	Strong	Biomarker	[8]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[27]
Head and neck cancer	DISBPSQZ	moderate	Altered Expression	[28]
Head and neck carcinoma	DISOU1DS	moderate	Altered Expression	[28]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[20]
Pulmonary tuberculosis	DIS6FLUM	moderate	Biomarker	[29]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[30]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[31]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[32]
Colorectal adenocarcinoma	DISPQOUB	Limited	Biomarker	[33]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[30]
Liver cancer	DISDE4BI	Limited	Biomarker	[31]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[34]
Seminoma	DIS3J8LJ	Limited	Altered Expression	[35]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[36]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

3 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 1 (PIWIL1).	[37]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Piwi-like protein 1 (PIWIL1).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Piwi-like protein 1 (PIWIL1).	[39]
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2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Piwi-like protein 1 (PIWIL1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Piwi-like protein 1 (PIWIL1).	[41]
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References

1	Expression of hiwi gene in human gastric cancer was associated with proliferation of cancer cells.Int J Cancer. 2006 Apr 15;118(8):1922-9. doi: 10.1002/ijc.21575.
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	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.
4	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.
5	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.
6	Molecular and Functional Characterization of the Somatic PIWIL1/piRNA Pathway in Colorectal Cancer Cells.Cells. 2019 Nov 5;8(11):1390. doi: 10.3390/cells8111390.
7	Aberrant Expression of PIWIL1 and PIWIL2 and Their Clinical Significance in Ductal Breast Carcinoma.Anticancer Res. 2018 Apr;38(4):2021-2030. doi: 10.21873/anticanres.12441.
8	Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
9	Piwil1 causes epigenetic alteration of PTEN gene via upregulation of DNA methyltransferase in type I endometrial cancer.Biochem Biophys Res Commun. 2015 Aug 7;463(4):876-80. doi: 10.1016/j.bbrc.2015.06.028. Epub 2015 Jun 6.
10	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.
11	PIWI-like protein 1 upregulation promotes gastric cancer invasion and metastasis.Onco Targets Ther. 2018 Dec 6;11:8783-8789. doi: 10.2147/OTT.S186827. eCollection 2018.
12	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.
13	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.
14	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.
15	Cancer-testis gene PIWIL1 promotes cell proliferation, migration, and invasion in lung adenocarcinoma.Cancer Med. 2018 Jan;7(1):157-166. doi: 10.1002/cam4.1248. Epub 2017 Nov 23.
16	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.
17	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.
18	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.
19	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.
20	The Prognosis Value of PIWIL1 and PIWIL2 Expression in Pancreatic Cancer.J Clin Med. 2019 Aug 22;8(9):1275. doi: 10.3390/jcm8091275.
21	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.
22	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.
23	The stem cell-associated Hiwi gene in human adenocarcinoma of the pancreas: expression and risk of tumour-related death.Br J Cancer. 2008 Oct 7;99(7):1083-8. doi: 10.1038/sj.bjc.6604653. Epub 2008 Sep 9.
24	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.
25	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.
26	Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma.Oncogene. 2007 Feb 15;26(7):1098-100. doi: 10.1038/sj.onc.1209880. Epub 2006 Sep 4.
27	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.
28	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.
29	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.
30	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.
31	Silencing HIWI suppresses the growth, invasion and migration of glioma cells.Int J Oncol. 2014 Dec;45(6):2385-92. doi: 10.3892/ijo.2014.2673. Epub 2014 Sep 25.
32	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.
33	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.
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	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.
36	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.
37	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.
38	Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
39	Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
40	CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
41	Global gene expression analysis reveals novel transcription factors associated with long-term low-level exposure of EA.hy926 human endothelial cells to bisphenol A. Chem Biol Interact. 2023 Aug 25;381:110571. doi: 10.1016/j.cbi.2023.110571. Epub 2023 May 25.