Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVXS2SM)

• DOT Name: Sperm-associated antigen 4 protein (SPAG4)
• Synonyms: Outer dense fiber-associated protein SPAG4; SUN domain-containing protein 4
• Gene Name: SPAG4
• Related Disease:
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Adult glioblastoma
  Advanced cancer
  Glioblastoma multiforme
  Kidney neoplasm
  Neoplasm
  Renal cell carcinoma
  Clear cell renal carcinoma
• UniProt ID: SPAG4_HUMAN
• Pfam ID: PF07738
• Sequence:
  MRRSSRPGSASSSRKHTPNFFSENSSMSITSEDSKGLRSAEPGPGEPEGRRARGPSCGEP
  ALSAGVPGGTTWAGSSQQKPAPRSHNWQTACGAATVRGGASEPTGSPVVSEEPLDLLPTL
  DLRQEMPPPRVFKSFLSLLFQGLSVLLSLAGDVLVSMYREVCSIRFLFTAVSLLSLFLSA
  FWLGLLYLVSPLENEPKEMLTLSEYHERVRSQGQQLQQLQAELDKLHKEVSTVRAANSER
  VAKLVFQRLNEDFVRKPDYALSSVGASIDLQKTSHDYADRNTAYFWNRFSFWNYARPPTV
  ILEPHVFPGNCWAFEGDQGQVVIQLPGRVQLSDITLQHPPPSVEHTGGANSAPRDFAVFG
  LQVYDETEVSLGKFTFDVEKSEIQTFHLQNDPPAAFPKVKIQILSNWGHPRFTCLYRVRA
  HGVRTSEGAEGSAQGPH
• Function: Involved in spermatogenesis. Required for sperm head formation but not required to establish and maintain general polarity of the sperm head. Required for anchoring and organization of the manchette. Required for targeting of SUN3 and probably SYNE1 through a probable SUN1:SYNE3 LINC complex to the nuclear envelope and involved in accurate posterior sperm head localization of the complex. May anchor SUN3 the nuclear envelope. Involved in maintenance of the nuclear envelope integrity. May assist the organization and assembly of outer dense fibers (ODFs), a specific structure of the sperm tail.
• Tissue Specificity: Predominantly epressed in testis. Expressed in ejaculated spermatozoa (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Limited	Altered Expression	[3]

1 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 Sperm-associated antigen 4 protein (SPAG4).	[5]

13 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 Sperm-associated antigen 4 protein (SPAG4).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sperm-associated antigen 4 protein (SPAG4).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sperm-associated antigen 4 protein (SPAG4).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sperm-associated antigen 4 protein (SPAG4).	[9]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Sperm-associated antigen 4 protein (SPAG4).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sperm-associated antigen 4 protein (SPAG4).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Sperm-associated antigen 4 protein (SPAG4).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sperm-associated antigen 4 protein (SPAG4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sperm-associated antigen 4 protein (SPAG4).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sperm-associated antigen 4 protein (SPAG4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Sperm-associated antigen 4 protein (SPAG4).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Sperm-associated antigen 4 protein (SPAG4).	[17]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Sperm-associated antigen 4 protein (SPAG4).	[10]

References

• [1] Spermassociated antigen 4 (SPAG4) as a new cancer marker interacts with Nesprin3 to regulate cell migration in lung carcinoma.Oncol Rep. 2018 Aug;40(2):783-792. doi: 10.3892/or.2018.6473. Epub 2018 Jun 4.
• [2] Human sperm-associated antigen 4 as a potential biomarker of glioblastoma progression and prognosis.Neuroreport. 2019 Apr 10;30(6):446-451. doi: 10.1097/WNR.0000000000001226.
• [3] Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro.Mol Carcinog. 2014 Dec;53(12):970-8. doi: 10.1002/mc.22065. Epub 2013 Jul 2.
• [4] Sperm-associated antigen 4, a novel hypoxia-inducible factor 1 target, regulates cytokinesis, and its expression correlates with the prognosis of renal cell carcinoma.Am J Pathol. 2013 Jun;182(6):2191-203. doi: 10.1016/j.ajpath.2013.02.024. Epub 2013 Apr 17.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [10] 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.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] 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.
• [17] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.