Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCYF466)

• DOT Name: Zinc transporter ZIP6 (SLC39A6)
• Synonyms: Estrogen-regulated protein LIV-1; Solute carrier family 39 member 6; Zrt- and Irt-like protein 6; ZIP-6
• Gene Name: SLC39A6
• UniProt ID: S39A6_HUMAN
• Pfam ID: PF02535
• Sequence:
  MARKLSVILILTFALSVTNPLHELKAAAFPQTTEKISPNWESGINVDLAISTRQYHLQQL
  FYRYGENNSLSVEGFRKLLQNIGIDKIKRIHIHHDHDHHSDHEHHSDHERHSDHEHHSEH
  EHHSDHDHHSHHNHAASGKNKRKALCPDHDSDSSGKDPRNSQGKGAHRPEHASGRRNVKD
  SVSASEVTSTVYNTVSEGTHFLETIETPRPGKLFPKDVSSSTPPSVTSKSRVSRLAGRKT
  NESVSEPRKGFMYSRNTNENPQECFNASKLLTSHGMGIQVPLNATEFNYLCPAIINQIDA
  RSCLIHTSEKKAEIPPKTYSLQIAWVGGFIAISIISFLSLLGVILVPLMNRVFFKFLLSF
  LVALAVGTLSGDAFLHLLPHSHASHHHSHSHEEPAMEMKRGPLFSHLSSQNIEESAYFDS
  TWKGLTALGGLYFMFLVEHVLTLIKQFKDKKKKNQKKPENDDDVEIKKQLSKYESQLSTN
  EEKVDTDDRTEGYLRADSQEPSHFDSQQPAVLEEEEVMIAHAHPQEVYNEYVPRGCKNKC
  HSHFHDTLGQSDDLIHHHHDYHHILHHHHHQNHHPHSHSQRYSREELKDAGVATLAWMVI
  MGDGLHNFSDGLAIGAAFTEGLSSGLSTSVAVFCHELPHELGDFAVLLKAGMTVKQAVLY
  NALSAMLAYLGMATGIFIGHYAENVSMWIFALTAGLFMYVALVDMVPEMLHNDASDHGCS
  RWGYFFLQNAGMLLGFGIMLLISIFEHKIVFRINF
• Function: Zinc-influx transporter which plays a role in zinc homeostasis and in the induction of epithelial-to-mesenchymal transition (EMT). When associated with SLC39A10, the heterodimer formed by SLC39A10 and SLC39A6 mediates cellular zinc uptake to trigger cells to undergo epithelial- to-mesenchymal transition (EMT). The SLC39A10-SLC39A6 heterodimer also controls NCAM1 phosphorylation and its integration into focal adhesion complexes during EMT. Zinc influx inactivates GSK3B, enabling unphosphorylated SNAI1 in the nucleus to down-regulate adherence genes such as CDH1, causing loss of cell adherence. In addition, the SLC39A10-SLC39A6 heterodimer plays an essentiel role in initiating mitosis by importing zinc into cells to initiate a pathway resulting in the onset of mitosis. Participates in the T-cell receptor signaling regulation by mediating cellular zinc uptake into activated lymphocytes. Regulates the zinc influx necessary for proper meiotic progression to metaphase II (MII) that allows the oocyte-to-egg transition.
• Tissue Specificity: Highly expressed in the breast, prostate, placenta, kidney, pituitary and corpus callosum . Weakly expressed in heart and intestine. Also highly expressed in cells derived from an adenocarcinoma of the cervix and lung carcinoma .
• KEGG Pathway:
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
• Reactome Pathway: Zinc influx into cells by the SLC39 gene family (R-HSA-442380)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Zinc transporter ZIP6 (SLC39A6) decreases the response to substance of Vorinostat.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Zinc transporter ZIP6 (SLC39A6).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Zinc transporter ZIP6 (SLC39A6).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Zinc transporter ZIP6 (SLC39A6).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Zinc transporter ZIP6 (SLC39A6).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[6]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Zinc transporter ZIP6 (SLC39A6).	[9]
Gallium nitrate	DMF9O6B	Approved	Gallium nitrate decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[10]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Zinc transporter ZIP6 (SLC39A6).	[11]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Zinc transporter ZIP6 (SLC39A6).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Zinc transporter ZIP6 (SLC39A6).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Zinc transporter ZIP6 (SLC39A6).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Zinc transporter ZIP6 (SLC39A6).	[16]
Apicidin	DM83WVF	Investigative	Apicidin increases the expression of Zinc transporter ZIP6 (SLC39A6).	[17]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [7] Cellular zinc homeostasis is a regulator in monocyte differentiation of HL-60 cells by 1 alpha,25-dihydroxyvitamin D3. J Leukoc Biol. 2010 May;87(5):833-44. doi: 10.1189/jlb.0409241. Epub 2010 Jan 20.
• [8] 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.
• [9] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [10] Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med. 2008 Sep 15;45(6):763-72.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [14] Bisphenol A stimulates the epithelial mesenchymal transition of estrogen negative breast cancer cells via FOXA1 signals. Arch Biochem Biophys. 2015 Nov 1;585:10-16. doi: 10.1016/j.abb.2015.09.006. Epub 2015 Sep 9.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [17] Identification of LIV1, a putative zinc transporter gene responsible for HDACi-induced apoptosis, using a functional gene screen approach. Mol Cancer Ther. 2009 Nov;8(11):3108-16. doi: 10.1158/1535-7163.MCT-08-0772. Epub 2009 Nov 3.