Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE8CE2E)

• DOT Name: FAS-associated factor 2 (FAF2)
• Synonyms: UBX domain-containing protein 3B; UBX domain-containing protein 8
• Gene Name: FAF2
• Related Disease:
  Atopic dermatitis
  Fatty liver disease
  Prostate cancer
  Prostate neoplasm
• UniProt ID: FAF2_HUMAN
• PDB ID: 2DAM
• Pfam ID: PF21021 ; PF14555 ; PF00789
• Sequence:
  MAAPEERDLTQEQTEKLLQFQDLTGIESMDQCRHTLEQHNWNIEAAVQDRLNEQEGVPSV
  FNPPPSRPLQVNTADHRIYSYVVSRPQPRGLLGWGYYLIMLPFRFTYYTILDIFRFALRF
  IRPDPRSRVTDPVGDIVSFMHSFEEKYGRAHPVFYQGTYSQALNDAKRELRFLLVYLHGD
  DHQDSDEFCRNTLCAPEVISLINTRMLFWACSTNKPEGYRVSQALRENTYPFLAMIMLKD
  RRMTVVGRLEGLIQPDDLINQLTFIMDANQTYLVSERLEREERNQTQVLRQQQDEAYLAS
  LRADQEKERKKREERERKRRKEEEVQQQKLAEERRRQNLQEEKERKLECLPPEPSPDDPE
  SVKIIFKLPNDSRVERRFHFSQSLTVIHDFLFSLKESPEKFQIEANFPRRVLPCIPSEEW
  PNPPTLQEAGLSHTEVLFVQDLTDE
• Function: Plays an important role in endoplasmic reticulum-associated degradation (ERAD) that mediates ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway. Involved in inhibition of lipid droplet degradation by binding to phospholipase PNPL2 and inhibiting its activity by promoting dissociation of PNPL2 from its endogenous activator, ABHD5 which inhibits the rate of triacylglycerol hydrolysis. Involved in stress granule disassembly: associates with ubiquitinated G3BP1 in response to heat shock, thereby promoting interaction between ubiquitinated G3BP1 and VCP, followed by G3BP1 extraction from stress granules and stress granule disassembly.
• Tissue Specificity: Broadly expressed, with highest levels in brain.
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[1]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of FAS-associated factor 2 (FAF2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of FAS-associated factor 2 (FAF2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FAS-associated factor 2 (FAF2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of FAS-associated factor 2 (FAF2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of FAS-associated factor 2 (FAF2).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of FAS-associated factor 2 (FAF2).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of FAS-associated factor 2 (FAF2).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of FAS-associated factor 2 (FAF2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of FAS-associated factor 2 (FAF2).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of FAS-associated factor 2 (FAF2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of FAS-associated factor 2 (FAF2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of FAS-associated factor 2 (FAF2).	[13]

References

• [1] Cloning and characterization of the highly expressed ETEA gene from blood cells of atopic dermatitis patients.Biochem Biophys Res Commun. 2002 Oct 11;297(5):1282-90. doi: 10.1016/s0006-291x(02)02380-x.
• [2] Hepatocyte-specific depletion of ubiquitin regulatory X domain containing protein 8 accelerates fibrosis in a mouse non-alcoholic steatohepatitis model.Histochem Cell Biol. 2017 Sep;148(3):219-227. doi: 10.1007/s00418-017-1572-6. Epub 2017 Apr 18.
• [3] Global analysis of differentially expressed genes in androgen-independent prostate cancer.Prostate Cancer Prostatic Dis. 2007;10(2):167-74. doi: 10.1038/sj.pcan.4500933. Epub 2007 Jan 2.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [13] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [14] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.