Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2VLWT0)

• DOT Name: P antigen family member 4 (PAGE4)
• Synonyms: PAGE-4; G antigen family C member 1; PAGE-1
• Gene Name: PAGE4
• Related Disease:
  Adult germ cell tumor
  Advanced cancer
  Benign prostatic hyperplasia
  Castration-resistant prostate carcinoma
  Germ cell tumor
  Germ cell tumour
  Gastric neoplasm
  Prostate cancer
  Prostate carcinoma
  Colorectal carcinoma
• UniProt ID: PAGE4_HUMAN
• PDB ID: 6URQ
• Pfam ID: PF05831
• Sequence:
  MSARVRSRSRGRGDGQEAPDVVAFVAPGESQQEEPPTDNQDIEPGQEREGTPPIEERKVE
  GDCQEMDLEKTRSERGDGSDVKEKTPPNPKHAKTKEAGDGQP
• Function: Intrinsically disordered protein that potentiates the transcriptional activator activity of JUN. Protects cells from stress-induced apoptosis by inhibiting reactive oxygen species (ROS) production and via regulation of the MAPK signaling pathway.
• Tissue Specificity: Expressed at basal lvels in the adult normal prostate gland but is highly up-regulated in the fetal prostate and prostate cancer cells . Preferentially expressed in normal male and female reproductive tissues, testis, fallopian tube, uterus, and placenta, as well as in testicular cancer, uterine cancer, cervical cancer and kidney cancer .

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult germ cell tumor	DISJUCQ7	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[2]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Altered Expression	[3]
Germ cell tumor	DIS62070	Strong	Biomarker	[1]
Germ cell tumour	DISOF3TK	Strong	Biomarker	[1]
Gastric neoplasm	DISOKN4Y	Disputed	Altered Expression	[4]
Prostate cancer	DISF190Y	Disputed	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of P antigen family member 4 (PAGE4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of P antigen family member 4 (PAGE4).	[15]

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 P antigen family member 4 (PAGE4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of P antigen family member 4 (PAGE4).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of P antigen family member 4 (PAGE4).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of P antigen family member 4 (PAGE4).	[11]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of P antigen family member 4 (PAGE4).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of P antigen family member 4 (PAGE4).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of P antigen family member 4 (PAGE4).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of P antigen family member 4 (PAGE4).	[16]

References

• [1] PAGE-1, an X chromosome-linked GAGE-like gene that is expressed in normal and neoplastic prostate, testis, and uterus.Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10757-62. doi: 10.1073/pnas.95.18.10757.
• [2] Profiling molecular targets of TGF-beta1 in prostate fibroblast-to-myofibroblast transdifferentiation.Mech Ageing Dev. 2005 Jan;126(1):59-69. doi: 10.1016/j.mad.2004.09.023.
• [3] Expression of cancer/testis antigens in prostate cancer is associated with disease progression.Prostate. 2010 Dec 1;70(16):1778-87. doi: 10.1002/pros.21214.
• [4] The expression of GAGE gene can predict aggressive biologic behavior of intestinal type of stomach cancer.Hepatogastroenterology. 2004 Sep-Oct;51(59):1519-23.
• [5] PAGE4 promotes prostate cancer cells survive under oxidative stress through modulating MAPK/JNK/ERK pathway.J Exp Clin Cancer Res. 2019 Jan 18;38(1):24. doi: 10.1186/s13046-019-1032-3.
• [6] Cancer/testis antigens and clinical risk factors for liver metastasis of colorectal cancer: a predictive panel.Dis Colon Rectum. 2010 Jan;53(1):31-8. doi: 10.1007/DCR.0b013e3181bdca3a.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.