Details of Drug Off-Target (DOT)

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

• DOT Name: Testis-expressed protein 11 (TEX11)
• Synonyms: Protein ZIP4 homolog; ZIP4H
• Gene Name: TEX11
• Related Disease:
  Advanced cancer
  Azoospermia
  Epithelial ovarian cancer
  Glioma
  Hepatocellular carcinoma
  Liver cancer
  Male infertility
  Metastatic malignant neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Prostate carcinoma
  Spermatogenic failure, X-linked, 2
  Epidermodysplasia verruciformis
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Nasopharyngeal carcinoma
  Pancreatic tumour
• UniProt ID: TEX11_HUMAN
• Pfam ID: PF08631
• Sequence:
  MISAHCNLRLLCSSDSSASASQVAGTTEVVENLVTNDNSPNIPEAIDRLFSDIANINRES
  MAEITDIQIEEMAVNLWNWALTIGGGWLVNEEQKIRLHYVACKLLSMCEASFASEQSIQR
  LIMMNMRIGKEWLDAGNFLIADECFQAAVASLEQLYVKLIQRSSPEADLTMEKITVESDH
  FRVLSYQAESAVAQGDFQRASMCVLQCKDMLMRLPQMTSSLHHLCYNFGVETQKNNKYEE
  SSFWLSQSYDIGKMDKKSTGPEMLAKVLRLLATNYLDWDDTKYYDKALNAVNLANKEHLS
  SPGLFLKMKILLKGETSNEELLEAVMEILHLDMPLDFCLNIAKLLMDHERESVGFHFLTI
  IHERFKSSENIGKVLILHTDMLLQRKEELLAKEKIEEIFLAHQTGRQLTAESMNWLHNIL
  WRQAASSFEVQNYTDALQWYYYSLRFYSTDEMDLDFTKLQRNMACCYLNLQQLDKAKEAV
  AEAERHDPRNVFTQFYIFKIAVIEGNSERALQAIITLENILTDEESEDNDLVAERGSPTM
  LLSLAAQFALENGQQIVAEKALEYLAQHSEDQEQVLTAVKCLLRFLLPKIAEMPESEDKK
  KEMDRLLTCLNRAFVKLSQPFGEEALSLESRANEAQWFRKTAWNLAVQCDKDPVMMREFF
  ILSYKMSQFCPSDQVILIARKTCLLMAVAVDLEQGRKASTAFEQTMFLSRALEEIQTCND
  IHNFLKQTGTFSNDSCEKLLLLYEFEVRAKLNDPLLESFLESVWELPHLETKTFETIAII
  AMEKPAHYPLIALKALKKALLLYKKEEPIDISQYSKCMHNLVNLSVPDGASNVELCPLEE
  VWGYFEDALSHISRTKDYPEMEILWLMVKSWNTGVLMFSRSKYASAEKWCGLALRFLNHL
  TSFKESYETQMNMLYSQLVEALSNNKGPVFHEHGYWSKSD
• Function: Regulator of crossing-over during meiosis. Involved in initiation and/or maintenance of chromosome synapsis and formation of crossovers.
• Tissue Specificity: Testis-specific. Not expressed in adult ovaries.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Azoospermia	DIS94181	Strong	Genetic Variation	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[8]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[8]
Pancreatic cancer	DISJC981	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Spermatogenic failure, X-linked, 2	DIS4L7UT	Strong	X-linked	[11]
Epidermodysplasia verruciformis	DIS54WBS	moderate	Biomarker	[12]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Supportive	Autosomal dominant	[13]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[14]
Pancreatic tumour	DIS3U0LK	Limited	Biomarker	[15]

4 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 Testis-expressed protein 11 (TEX11).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Testis-expressed protein 11 (TEX11).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Testis-expressed protein 11 (TEX11).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Testis-expressed protein 11 (TEX11).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Testis-expressed protein 11 (TEX11).	[20]

References

• [1] ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism.Clin Cancer Res. 2018 Jul 1;24(13):3186-3196. doi: 10.1158/1078-0432.CCR-18-0263. Epub 2018 Apr 3.
• [2] A novel TEX11 mutation induces azoospermia: a case report of infertile brothers and literature review.BMC Med Genet. 2018 Apr 16;19(1):63. doi: 10.1186/s12881-018-0570-4.
• [3] Changes in mRNA/protein expression and signaling pathways in in vivo passaged mouse ovarian cancer cells.PLoS One. 2018 Jun 21;13(6):e0197404. doi: 10.1371/journal.pone.0197404. eCollection 2018.
• [4] ZIP4 is a novel molecular marker for glioma.Neuro Oncol. 2013 Aug;15(8):1008-16. doi: 10.1093/neuonc/not042. Epub 2013 Apr 17.
• [5] Zip4 (Slc39a4) expression is activated in hepatocellular carcinomas and functions to repress apoptosis, enhance cell cycle and increase migration.PLoS One. 2010 Oct 4;5(10):e13158. doi: 10.1371/journal.pone.0013158.
• [6] Novel mechanism of aberrant ZIP4 expression with zinc supplementation in oral tumorigenesis.Biochem Biophys Res Commun. 2017 Jan 29;483(1):339-345. doi: 10.1016/j.bbrc.2016.12.142. Epub 2016 Dec 23.
• [7] Down-regulation of ZIP4 by RNA interference inhibits pancreatic cancer growth and increases the survival of nude mice with pancreatic cancer xenografts.Clin Cancer Res. 2009 Oct 1;15(19):5993-6001. doi: 10.1158/1078-0432.CCR-09-0557. Epub 2009 Sep 15.
• [8] The novel ZIP4 regulation and its role in ovarian cancer.Oncotarget. 2017 Sep 30;8(52):90090-90107. doi: 10.18632/oncotarget.21435. eCollection 2017 Oct 27.
• [9] ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin 31 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells.Gastroenterology. 2020 Feb;158(3):679-692.e1. doi: 10.1053/j.gastro.2019.10.038. Epub 2019 Nov 9.
• [10] The role of zinc transporter ZIP4 in prostate carcinoma.Urol Oncol. 2012 Nov-Dec;30(6):906-11. doi: 10.1016/j.urolonc.2010.11.010. Epub 2011 Jul 30.
• [11] Meiotic failure in male mice lacking an X-linked factor. Genes Dev. 2008 Mar 1;22(5):682-91. doi: 10.1101/gad.1613608.
• [12] Zinc and Skin Disorders.Nutrients. 2018 Feb 11;10(2):199. doi: 10.3390/nu10020199.
• [13] X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med. 2015 May 28;372(22):2097-107. doi: 10.1056/NEJMoa1406192. Epub 2015 May 13.
• [14] Inhibition of ZIP4 reverses epithelial-to-mesenchymal transition and enhances the radiosensitivity in human nasopharyngeal carcinoma cells.Cell Death Dis. 2019 Aug 5;10(8):588. doi: 10.1038/s41419-019-1807-7.
• [15] ZIP4 Promotes Muscle Wasting and Cachexia in Mice With Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells.Gastroenterology. 2019 Feb;156(3):722-734.e6. doi: 10.1053/j.gastro.2018.10.026. Epub 2018 Oct 17.
• [16] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [20] 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.