Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3SYRUJ)

• DOT Name: Placenta-specific gene 8 protein (PLAC8)
• Synonyms: Protein C15
• Gene Name: PLAC8
• Related Disease:
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Mycoses
  Pancreatic cancer
  Matthew-Wood syndrome
  Non-small-cell lung cancer
  Clear cell renal carcinoma
  Kidney cancer
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Atrial septal defect
  Autism spectrum disorder
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Gallbladder carcinoma
  Nasopharyngeal carcinoma
  Nasopharyngitis
  Osteosarcoma
  Patent ductus arteriosus
• UniProt ID: PLAC8_HUMAN
• Pfam ID: PF04749
• Sequence:
  MQAQAPVVVVTQPGVGPGPAPQNSNWQTGMCDCFSDCGVCLCGTFCFPCLGCQVAADMNE
  CCLCGTSVAMRTLYRTRYGIPGSICDDYMATLCCPHCTLCQIKRDINRRRAMRTF
• Tissue Specificity: Expressed at high levels in plasmacytoid dendritic cells. High expression in spleen, lymph nodes, peripheral blood leukocytes, and bone marrow, with lower expression in thymus, appendix, and fetal liver.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[2]
Lung cancer	DISCM4YA	Definitive	Biomarker	[3]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[3]
Mycoses	DIS9K7PB	Definitive	Altered Expression	[4]
Pancreatic cancer	DISJC981	Definitive	Biomarker	[5]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[7]
Kidney cancer	DISBIPKM	moderate	Biomarker	[8]
Prostate cancer	DISF190Y	moderate	Biomarker	[9]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[9]
Renal carcinoma	DISER9XT	moderate	Biomarker	[8]
Atrial septal defect	DISJT76B	Limited	Altered Expression	[10]
Autism spectrum disorder	DISXK8NV	Limited	Altered Expression	[10]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[11]
Breast cancer	DIS7DPX1	Limited	Biomarker	[12]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[12]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[13]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[14]
Nasopharyngitis	DISVLL0V	Limited	Altered Expression	[14]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[11]
Patent ductus arteriosus	DIS9P8YS	Limited	Biomarker	[15]

2 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 Placenta-specific gene 8 protein (PLAC8).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Placenta-specific gene 8 protein (PLAC8).	[25]

14 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 Placenta-specific gene 8 protein (PLAC8).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Placenta-specific gene 8 protein (PLAC8).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Placenta-specific gene 8 protein (PLAC8).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Placenta-specific gene 8 protein (PLAC8).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Placenta-specific gene 8 protein (PLAC8).	[21]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Placenta-specific gene 8 protein (PLAC8).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Placenta-specific gene 8 protein (PLAC8).	[23]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Placenta-specific gene 8 protein (PLAC8).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Placenta-specific gene 8 protein (PLAC8).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Placenta-specific gene 8 protein (PLAC8).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Placenta-specific gene 8 protein (PLAC8).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Placenta-specific gene 8 protein (PLAC8).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Placenta-specific gene 8 protein (PLAC8).	[30]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Placenta-specific gene 8 protein (PLAC8).	[31]

References

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• [2] Placenta-specific protein 8 promotes the proliferation of lung adenocarcinoma PC-9 cells and their tolerance to an epidermal growth factor receptor tyrosine kinase inhibitor by activating the ERK signaling pathway.Oncol Lett. 2019 Nov;18(5):5621-5627. doi: 10.3892/ol.2019.10911. Epub 2019 Sep 24.
• [3] The novel KLF4/PLAC8 signaling pathway regulates lung cancer growth.Cell Death Dis. 2018 May 22;9(6):603. doi: 10.1038/s41419-018-0580-3.
• [4] Yeast expression of mammalian Onzin and fungal FCR1 suggests ancestral functions of PLAC8 proteins in mitochondrial metabolism and DNA repair.Sci Rep. 2019 Apr 29;9(1):6629. doi: 10.1038/s41598-019-43136-3.
• [5] PLAC8 Localizes to the Inner Plasma Membrane of Pancreatic Cancer Cells and Regulates Cell Growth and Disease Progression through Critical Cell-Cycle Regulatory Pathways.Cancer Res. 2016 Jan 1;76(1):96-107. doi: 10.1158/0008-5472.CAN-15-0216. Epub 2015 Dec 15.
• [6] Placenta-specific 8 is a potential novel target for osimertinib resistance in non-small cell lung cancer.Oncol Lett. 2019 Jul;18(1):955-961. doi: 10.3892/ol.2019.10344. Epub 2019 May 13.
• [7] Overexpression of placenta specific 8 is associated with malignant progression and poor prognosis of clear cell renal cell carcinoma.Int Urol Nephrol. 2017 Jul;49(7):1165-1176. doi: 10.1007/s11255-017-1578-y. Epub 2017 Mar 27.
• [8] Knockout of the Placenta Specific 8 Gene Affects the Proliferation and Migration of Human Embryonic Kidney 293T Cell.Cell Biochem Biophys. 2020 Mar;78(1):55-64. doi: 10.1007/s12013-019-00893-2. Epub 2019 Nov 6.
• [9] Induction of retinol-binding protein 4 and placenta-specific 8 expression in human prostate cancer cells remaining in bone following osteolytic tumor growth inhibition by osteoprotegerin.Int J Oncol. 2013 Aug;43(2):365-74. doi: 10.3892/ijo.2013.1954. Epub 2013 May 24.
• [10] Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease.J Immunol. 2018 Dec 15;201(12):3534-3545. doi: 10.4049/jimmunol.1800667. Epub 2018 Nov 7.
• [11] ONZIN Upregulation by Mutant p53 Contributes to Osteosarcoma Metastasis Through the CXCL5-MAPK Signaling Pathway.Cell Physiol Biochem. 2018;48(3):1099-1111. doi: 10.1159/000491976. Epub 2018 Jul 24.
• [12] PLCA8 suppresses breast cancer apoptosis by activating the PI3k/AKT/NF-B pathway.J Cell Mol Med. 2019 Oct;23(10):6930-6941. doi: 10.1111/jcmm.14578. Epub 2019 Aug 26.
• [13] PLAC8 overexpression correlates with PD-L1 upregulation and acquired resistance to chemotherapies in gallbladder carcinoma.Biochem Biophys Res Commun. 2019 Aug 27;516(3):983-990. doi: 10.1016/j.bbrc.2019.06.121. Epub 2019 Jul 2.
• [14] Placenta specific 8 gene induces epithelial-mesenchymal transition of nasopharyngeal carcinoma cells via the TGF-/Smad pathway.Exp Cell Res. 2019 Jan 1;374(1):172-180. doi: 10.1016/j.yexcr.2018.11.021. Epub 2018 Nov 26.
• [15] Plac8 links oncogenic mutations to regulation of autophagy and is critical to pancreatic cancer progression.Cell Rep. 2014 May 22;7(4):1143-55. doi: 10.1016/j.celrep.2014.03.061. Epub 2014 May 1.
• [16] 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.
• [17] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [18] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [22] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [25] 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.
• [26] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [31] 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.