Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHQW98S)

• DOT Name: Paternally-expressed gene 3 protein (PEG3)
• Synonyms: Zinc finger and SCAN domain-containing protein 24
• Gene Name: PEG3
• Related Disease:
  Advanced cancer
  Fetal growth restriction
  Anxiety
  Anxiety disorder
  Breast cancer
  Cervical cancer
  Cervical carcinoma
  Choriocarcinoma
  Colon cancer
  Colon carcinoma
  Complete hydatidiform mole
  Depression
  Germ cell tumor
  Gestational trophoblastic neoplasia
  Glioma
  Melanoma
  Muscular dystrophy
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Oropharyngeal cancer
  Oropharyngeal carcinoma
  Oropharyngeal squamous cell carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Prostate neoplasm
  Testicular germ cell tumor
  Gynecologic cancer
  Neuroblastoma
  Acute myelogenous leukaemia
  Breast carcinoma
  Cervical Intraepithelial neoplasia
  Cholangiocarcinoma
  Human papillomavirus infection
  Intrahepatic cholangiocarcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: PEG3_HUMAN
• PDB ID: 4BHX
• Pfam ID: PF02023 ; PF00096
• Sequence:
  MLPPKHLSATKPKKSWAPNLYELDSDLTKEPDVIIGEGPTDSEFFHQRFRNLIYVEFVGP
  RKTLIKLRNLCLDWLQPETRTKEEIIELLVLEQYLTIIPEKLKPWVRAKKPENCEKLVTL
  LENYKEMYQPEDDNNSDVTSDDDMTRNRRESSPPHSVHSFSDRDWDRRGRSRDMEPRDRW
  SHTRNPRSRMPPRDLSLPVVAKTSFEMDREDDRDSRAYESRSQDAESYQNVVDLAEDRKP
  HNTIQDNMENYRKLLSLVQLAEDDGHSHMTQGHSSRSKRSAYPSTSRGLKTMPEAKKSTH
  RRGICEDESSHGVIMEKFIKDVSRSSKSGRARESSDRSQRFPRMSDDNWKDISLNKRESV
  IQQRVYEGNAFRGGFRFNSTLVSRKRVLERKRRYHFDTDGKGSIHDQKGCPRKKPFECGS
  EMRKAMSVSSLSSLSSPSFTESQPIDFGAMPYVCDECGRSFSVISEFVEHQIMHTRENLY
  EYGESFIHSVAVSEVQKSQVGGKRFECKDCGETFNKSAALAEHRKIHARGYLVECKNQEC
  EEAFMPSPTFSELQKIYGKDKFYECRVCKETFLHSSALIEHQKIHFGDDKDNEREHERER
  ERERGETFRPSPALNEFQKMYGKEKMYECKVCGETFLHSSSLKEHQKIHTRGNPFENKGK
  VCEETFIPGQSLKRRQKTYNKEKLCDFTDGRDAFMQSSELSEHQKIHSRKNLFEGRGYEK
  SVIHSGPFTESQKSHTITRPLESDEDEKAFTISSNPYENQKIPTKENVYEAKSYERSVIH
  SLASVEAQKSHSVAGPSKPKVMAESTIQSFDAINHQRVRAGGNTSEGREYSRSVIHSLVA
  SKPPRSHNGNELVESNEKGESSIYISDLNDKRQKIPARENPCEGGSKNRNYEDSVIQSVF
  RAKPQKSVPGEGSGEFKKDGEFSVPSSNVREYQKARAKKKYIEHRSNETSVIHSLPFGEQ
  TFRPRGMLYECQECGECFAHSSDLTEHQKIHDREKPSGSRNYEWSVIRSLAPTDPQTSYA
  QEQYAKEQARNKCKDFRQFFATSEDLNTNQKIYDQEKSHGEESQGENTDGEETHSEETHG
  QETIEDPVIQGSDMEDPQKDDPDDKIYECEDCGLGFVDLTDLTDHQKVHSRKCLVDSREY
  THSVIHTHSISEYQRDYTGEQLYECPKCGESFIHSSFLFEHQRIHEQDQLYSMKGCDDGF
  IALLPMKPRRNRAAERNPALAGSAIRCLLCGQGFIHSSALNEHMRLHREDDLLEQSQMAE
  EAIIPGLALTEFQRSQTEERLFECAVCGESFVNPAELADHVTVHKNEPYEYGSSYTHTSF
  LTEPLKGAIPFYECKDCGKSFIHSTVLTKHKELHLEEEEEDEAAAAAAAAAQEVEANVHV
  PQVVLRIQGLNVEAAEPEVEAAEPEVEAAEPEVEAAEPNGEAEGPDGEAAEPIGEAGQPN
  GEAEQPNGDADEPDGAGIEDPEERAEEPEGKAEEPEGDADEPDGVGIEDPEEGEDQEIQV
  EEPYYDCHECTETFTSSTAFSEHLKTHASMIIFEPANAFGECSGYIERASTSTGGANQAD
  EKYFKCDVCGQLFNDRLSLARHQNTHTG
• Function: Induces apoptosis in cooperation with SIAH1A. Acts as a mediator between p53/TP53 and BAX in a neuronal death pathway that is activated by DNA damage. Acts synergistically with TRAF2 and inhibits TNF induced apoptosis through activation of NF-kappa-B. Possesses a tumor suppressing activity in glioma cells.
• Tissue Specificity: Brain, glial cells, astrocytes, embryo, placenta, testis, ovary and uterus. In the placenta it is found in the layer of villous cytotrophoblast cells while in the ovary it is found in the cells of the ovarian stroma including the thecal layers around the follicles. Expression is highly repressed in glioma cell lines.

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Fetal growth restriction	DIS5WEJ5	Definitive	Biomarker	[2]
Anxiety	DISIJDBA	Strong	Biomarker	[3]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Choriocarcinoma	DISDBVNL	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Complete hydatidiform mole	DIS5QPI0	Strong	Altered Expression	[8]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Germ cell tumor	DIS62070	Strong	Altered Expression	[9]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Altered Expression	[8]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[12]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[13]
Obesity	DIS47Y1K	Strong	Altered Expression	[14]
Oropharyngeal cancer	DISDAMTJ	Strong	Posttranslational Modification	[15]
Oropharyngeal carcinoma	DIS7K3AI	Strong	Posttranslational Modification	[15]
Oropharyngeal squamous cell carcinoma	DIS7D7QV	Strong	Biomarker	[15]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[16]
Ovarian neoplasm	DISEAFTY	Strong	Posttranslational Modification	[16]
Pancreatic cancer	DISJC981	Strong	Biomarker	[17]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[18]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[9]
Gynecologic cancer	DIST2NIJ	moderate	Altered Expression	[6]
Neuroblastoma	DISVZBI4	moderate	Genetic Variation	[19]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[20]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[12]
Cervical Intraepithelial neoplasia	DISXP757	Limited	Posttranslational Modification	[21]
Cholangiocarcinoma	DIS71F6X	Limited	Biomarker	[22]
Human papillomavirus infection	DISX61LX	Limited	Genetic Variation	[21]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Limited	Biomarker	[22]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[23]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[23]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[23]

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 Paternally-expressed gene 3 protein (PEG3).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Paternally-expressed gene 3 protein (PEG3).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Paternally-expressed gene 3 protein (PEG3).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Paternally-expressed gene 3 protein (PEG3).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Paternally-expressed gene 3 protein (PEG3).	[26]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Paternally-expressed gene 3 protein (PEG3).	[27]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Paternally-expressed gene 3 protein (PEG3).	[28]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Paternally-expressed gene 3 protein (PEG3).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Paternally-expressed gene 3 protein (PEG3).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Paternally-expressed gene 3 protein (PEG3).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Paternally-expressed gene 3 protein (PEG3).	[34]

References

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• [2] Alterations to DNA structure as a cause of expression modifications of selected genes of known intrauterine-growth-restriction-association shared by chosen species - a review.Anim Genet. 2019 Dec;50(6):613-620. doi: 10.1111/age.12861. Epub 2019 Oct 1.
• [3] Loss of offspring Peg3 reduces neonatal ultrasonic vocalizations and increases maternal anxiety in wild-type mothers.Hum Mol Genet. 2018 Feb 1;27(3):440-450. doi: 10.1093/hmg/ddx412.
• [4] Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression.Nat Med. 2011 Jan;17(1):123-9. doi: 10.1038/nm.2269. Epub 2010 Dec 12.
• [5] Long noncoding RNA ZNF667-AS1 reduces tumor invasion and metastasis in cervical cancer by counteracting microRNA-93-3p-dependent PEG3 downregulation.Mol Oncol. 2019 Nov;13(11):2375-2392. doi: 10.1002/1878-0261.12565. Epub 2019 Oct 17.
• [6] Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines.Gynecol Oncol. 2005 Oct;99(1):126-34. doi: 10.1016/j.ygyno.2005.05.036.
• [7] The role of PEG3 in the occurrence and prognosis of colon cancer.Onco Targets Ther. 2019 Jul 25;12:6001-6012. doi: 10.2147/OTT.S208060. eCollection 2019.
• [8] Identification of multiple differentially expressed messenger RNAs in normal and pathological trophoblast.Placenta. 2003 Feb-Mar;24(2-3):209-18. doi: 10.1053/plac.2002.0885.
• [9] Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors.Cell Death Dis. 2017 May 4;8(5):e2759. doi: 10.1038/cddis.2016.464.
• [10] The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth.J Biol Chem. 2010 Mar 12;285(11):8472-80. doi: 10.1074/jbc.M109.069450. Epub 2010 Jan 11.
• [11] PW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence.Nat Commun. 2015 Mar 9;6:6364. doi: 10.1038/ncomms7364.
• [12] Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis.J Biol Chem. 2017 Mar 24;292(12):5055-5069. doi: 10.1074/jbc.M116.753632. Epub 2017 Feb 7.
• [13] DNA methylation of candidate genes in peripheral blood from patients with type 2 diabetes or the metabolic syndrome.PLoS One. 2017 Jul 20;12(7):e0180955. doi: 10.1371/journal.pone.0180955. eCollection 2017.
• [14] Gene expression and epigenetic aberrations in F1-placentas fathered by obese males.Mol Reprod Dev. 2017 Apr;84(4):316-328. doi: 10.1002/mrd.22784. Epub 2017 Mar 3.
• [15] Hypermethylation of a cluster of Krppel-type zinc finger protein genes on chromosome 19q13 in oropharyngeal squamous cell carcinoma.Am J Pathol. 2011 May;178(5):1965-74. doi: 10.1016/j.ajpath.2011.01.049.
• [16] Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation.Cancer. 2008 Apr 1;112(7):1489-502. doi: 10.1002/cncr.23323.
• [17] Targeted virus replication plus immunotherapy eradicates primary and distant pancreatic tumors in nude mice.Cancer Res. 2005 Oct 1;65(19):9056-63. doi: 10.1158/0008-5472.CAN-05-1261.
• [18] Androgens down-regulate the expression of the human homologue of paternally expressed gene-3 in the prostatic adenocarcinoma cell line LNCaP.Mol Cell Endocrinol. 1999 Sep 10;155(1-2):69-76. doi: 10.1016/s0303-7207(99)00113-6.
• [19] Adenovirus-mediated hPNPase(old-35) gene transfer as a therapeutic strategy for neuroblastoma.J Cell Physiol. 2009 Jun;219(3):707-15. doi: 10.1002/jcp.21719.
• [20] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [21] Associations between methylation of paternally expressed gene 3 (PEG3), cervical intraepithelial neoplasia and invasive cervical cancer.PLoS One. 2013;8(2):e56325. doi: 10.1371/journal.pone.0056325. Epub 2013 Feb 13.
• [22] Exome sequencing of liver fluke-associated cholangiocarcinoma.Nat Genet. 2012 May 6;44(6):690-3. doi: 10.1038/ng.2273.
• [23] Therapeutic effects of adenovirus-mediated CD and NIS expression combined with Na(131)I/5-FC on human thyroid cancer.Oncol Lett. 2017 Dec;14(6):7431-7436. doi: 10.3892/ol.2017.7175. Epub 2017 Oct 12.
• [24] 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.
• [25] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [26] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [27] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [28] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [29] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [30] 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.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [33] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [34] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.