Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1PXQIF)

• DOT Name: Piwi-like protein 2 (PIWIL2)
• Synonyms: EC 3.1.26.-; Cancer/testis antigen 80; CT80
• Gene Name: PIWIL2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Adrenoleukodystrophy
  Advanced cancer
  Alcoholic liver diseases
  Breast disorder
  Carcinoma
  Cervical cancer
  Cholangiocarcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Dilated cardiomyopathy 1A
  Ductal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Germ cell tumor
  Glioma
  Leukoplakia
  Liver cirrhosis
  Male infertility
  Neoplasm
  Non-alcoholic fatty liver disease
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Oral cancer
  Oral mucosa leukoplakia
  Osteoarthritis
  Precancerous condition
  Promyelocytic leukaemia
  Rheumatoid arthritis
  Seminoma
  Testicular cancer
  Testicular germ cell tumor
  Urinary bladder cancer
  Urinary bladder neoplasm
  Hepatocellular carcinoma
  Pancreatic cancer
  Recessive X-linked ichthyosis
  Sarcoma
  Soft tissue sarcoma
  Coeliac disease
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
• UniProt ID: PIWL2_HUMAN
• PDB ID: 3O7X; 3QIR
• EC Number: 3.1.26.-
• Pfam ID: PF08699 ; PF02170 ; PF02171
• Sequence:
  MDPFRPSFRGQSPIHPSQCQAVRMPGCWPQASKPLDPALGRGAPAGRGHVFGKPEEPSTQ
  RGPAQRESVGLVSMFRGLGIETVSKTPLKREMLPSGRGILGRGLSANLVRKDREELSPTF
  WDPKVLAAGDSKMAETSVGWSRTLGRGSSDASLLPLGRAAGGISREVDKPPCTFSTPSRG
  PPQLSSPPALPQSPLHSPDRPLVLTVEHKEKELIVKQGSKGTPQSLGLNLVKIQCHNEAV
  YQYHVTFSPNVECKSMRFGMLKDHQAVTGNVTAFDGSILYLPVKLQQVLELKSQRKTDSA
  EISIKIQMTKILEPCSDLCIPFYNVVFRRVMKLLDMKLVGRNFYDPTSAMVLQQHRLQIW
  PGYAASIRRTDGGLFLLADVSHKVIRNDCVLDVMHAIYQQNKEHFQDECTKLLVGNIVIT
  RYNNRTYRIDDVDWNKTPKDSFTMSDGKEITFLEYYSKNYGITVKEEDQPLLIHRPSERQ
  DNHGMLLKGEILLLPELSFMTGIPEKMKKDFRAMKDLAQQINLSPKQHHSALECLLQRIA
  KNEAATNELMRWGLRLQKDVHKIEGRVLPMERINLKNTSFITSQELNWVKEVTRDPSILT
  IPMHFWALFYPKRAMDQARELVNMLEKIAGPIGMRMSPPAWVELKDDRIETYVRTIQSTL
  GAEGKIQMVVCIIMGPRDDLYGAIKKLCCVQSPVPSQVVNVRTIGQPTRLRSVAQKILLQ
  INCKLGGELWGVDIPLKQLMVIGMDVYHDPSRGMRSVVGFVASINLTLTKWYSRVVFQMP
  HQEIVDSLKLCLVGSLKKFYEVNHCLPEKIVVYRDGVSDGQLKTVANYEIPQLQKCFEAF
  ENYQPKMVVFVVQKKISTNLYLAAPQNFVTPTPGTVVDHTITSCEWVDFYLLAHHVRQGC
  GIPTHYVCVLNTANLSPDHMQRLTFKLCHMYWNWPGTIRVPAPCKYAHKLAFLSGHILHH
  EPAIQLCENLFFL
• Function: Endoribonuclease that plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Plays an essential role in meiotic differentiation of spermatocytes, germ cell differentiation and in self-renewal of spermatogonial stem cells. 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 govern the methylation and subsequent repression of transposons. During piRNA biosynthesis, plays a key role in the piRNA amplification loop, also named ping-pong amplification cycle, by acting as a 'slicer-competent' piRNA endoribonuclease that cleaves primary piRNAs, which are then loaded onto 'slicer-incompetent' PIWIL4. PIWIL2 slicing produces a pre-miRNA intermediate, which is then processed in mature piRNAs, and as well as a 16 nucleotide by-product that is degraded. Required for PIWIL4/MIWI2 nuclear localization and association with secondary piRNAs antisense. Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation. Indirectly modulates expression of genes such as PDGFRB, SLC2A1, ITGA6, GJA7, THY1, CD9 and STRA8. When overexpressed, acts as an oncogene by inhibition of apoptosis and promotion of proliferation in tumors. Represses circadian rhythms by promoting the stability and activity of core clock components BMAL1 and CLOCK by inhibiting GSK3B-mediated phosphorylation and ubiquitination-dependent degradation of these proteins.
• Tissue Specificity: Expressed in adult testis and in most tumors.
• Reactome Pathway: PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Adrenoleukodystrophy	DISTUD1F	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alcoholic liver diseases	DISXEPHQ	Strong	Biomarker	[2]
Breast disorder	DISJTGMA	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[1]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[1]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Germ cell tumor	DIS62070	Strong	Altered Expression	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Leukoplakia	DIST3QD3	Strong	Altered Expression	[3]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[2]
Male infertility	DISY3YZZ	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[13]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[2]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Strong	Autosomal recessive	[14]
Oral cancer	DISLD42D	Strong	Biomarker	[3]
Oral mucosa leukoplakia	DISJTL5X	Strong	Biomarker	[3]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Precancerous condition	DISV06FL	Strong	Altered Expression	[3]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[16]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[15]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[9]
Testicular cancer	DIS6HNYO	Strong	Biomarker	[17]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[18]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[18]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[19]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[13]
Recessive X-linked ichthyosis	DISZY56W	moderate	Biomarker	[20]
Sarcoma	DISZDG3U	moderate	Biomarker	[20]
Soft tissue sarcoma	DISSN8XB	moderate	Biomarker	[20]
Coeliac disease	DISIY60C	Limited	Biomarker	[21]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[5]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[5]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[5]

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Piwi-like protein 2 (PIWIL2).	[22]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Piwi-like protein 2 (PIWIL2).	[23]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Piwi-like protein 2 (PIWIL2).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Piwi-like protein 2 (PIWIL2).	[25]

References

• [1] 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.
• [2] Association between the concurrence of pre-existing chronic liver disease and worse prognosis in patients with an herb- Polygonum multiflorum thunb. induced liver injury: a case-control study from a specialised liver disease center in China.BMJ Open. 2019 Jan 15;9(1):e023567. doi: 10.1136/bmjopen-2018-023567.
• [3] Expression of PIWIL2 in oral cancer and leukoplakia: Prognostic implications and insights from tumors.Cancer Biomark. 2019;26(1):11-20. doi: 10.3233/CBM-182009.
• [4] Pathways of proliferation and antiapoptosis driven in breast cancer stem cells by stem cell protein piwil2.Cancer Res. 2010 Jun 1;70(11):4569-79. doi: 10.1158/0008-5472.CAN-09-2670. Epub 2010 May 11.
• [5] Differential expression of PIWIL2 in papillary thyroid cancers.Gene. 2018 Apr 5;649:8-13. doi: 10.1016/j.gene.2018.01.066. Epub 2018 Jan 31.
• [6] Expression and clinical significance of PIWIL2 in hilar cholangiocarcinoma tissues and cell lines.Genet Mol Res. 2015 Jun 26;14(2):7053-61. doi: 10.4238/2015.June.26.15.
• [7] Piwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity.Exp Biol Med (Maywood). 2012 Oct;237(10):1231-40. doi: 10.1258/ebm.2012.011380. Epub 2012 Oct 26.
• [8] Correlation of HIWI and HILI Expression with Cancer Stem Cell Markers in Colorectal Cancer.Anticancer Res. 2015 Jun;35(6):3317-24.
• [9] Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway.Hum Mol Genet. 2006 Jan 15;15(2):201-11. doi: 10.1093/hmg/ddi430. Epub 2005 Dec 23.
• [10] Expression profiles of PIWIL2 short isoforms differ in testicular germ cell tumors of various differentiation subtypes.PLoS One. 2014 Nov 10;9(11):e112528. doi: 10.1371/journal.pone.0112528. eCollection 2014.
• [11] High expression of PIWIL2 promotes tumor cell proliferation, migration and predicts a poor prognosis in glioma.Oncol Rep. 2017 Jul;38(1):183-192. doi: 10.3892/or.2017.5647. Epub 2017 May 17.
• [12] 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.
• [13] The Prognosis Value of PIWIL1 and PIWIL2 Expression in Pancreatic Cancer.J Clin Med. 2019 Aug 22;8(9):1275. doi: 10.3390/jcm8091275.
• [14] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [15] 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.
• [16] Per- and polyfluoroalkyl substances impact human spermatogenesis in a stem-cell-derived model.Syst Biol Reprod Med. 2018 Aug;64(4):225-239. doi: 10.1080/19396368.2018.1481465. Epub 2018 Jun 18.
• [17] The immunogenicity of a novel cytotoxic T lymphocyte epitope from tumor antigen PL2L60 could be enhanced by 4-chlorophenylalanine substitution at position 1.Cancer Immunol Immunother. 2013 Nov;62(11):1723-32. doi: 10.1007/s00262-013-1478-7.
• [18] Piwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients.Mol Med. 2015 May 13;21(1):371-80. doi: 10.2119/molmed.2014.00250.
• [19] Co-expression of Piwil2/Piwil4 in nucleus indicates poor prognosis of hepatocellular carcinoma.Oncotarget. 2017 Jan 17;8(3):4607-4617. doi: 10.18632/oncotarget.13491.
• [20] Expression of human Piwi-like genes is associated with prognosis for soft tissue sarcoma patients.BMC Cancer. 2012 Jun 29;12:272. doi: 10.1186/1471-2407-12-272.
• [21] Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies.Cell Mol Life Sci. 2018 Dec;75(23):4385-4401. doi: 10.1007/s00018-018-2898-5. Epub 2018 Aug 10.
• [22] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [23] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [24] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.