Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAN7RY5)

• DOT Name: Teashirt homolog 3 (TSHZ3)
• Synonyms: Zinc finger protein 537
• Gene Name: TSHZ3
• Related Disease:
  Adenoma
  Adult glioblastoma
  Autism
  Breast cancer
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Glioblastoma multiforme
  Glioma
  Intervertebral disc degeneration
  Neoplasm
  Non-insulin dependent diabetes
  Pervasive developmental disorder
  Prostate cancer
  Prostate carcinoma
  Trichohepatoenteric syndrome
  Autism spectrum disorder
  Congenital anomaly of kidney and urinary tract
• UniProt ID: TSH3_HUMAN
• PDB ID: 2DMI
• Pfam ID: PF13912
• Sequence:
  MPRRKQQAPRRAAAYVSEELKAAALVDEGLDPEEHTADGEPSAKYMCPEKELARACPSYQ
  NSPAAEFSCHEMDSESHISETSDRMADFESGSIKNEEETKEVTVPLEDTTVSDSLEQMKA
  VYNNFLSNSYWSNLNLNLHQPSSEKNNGSSSSSSSSSSSCGSGSFDWHQSAMAKTLQQVS
  QSRMLPEPSLFSTVQLYRQSSKLYGSIFTGASKFRCKDCSAAYDTLVELTVHMNETGHYR
  DDNHETDNNNPKRWSKPRKRSLLEMEGKEDAQKVLKCMYCGHSFESLQDLSVHMIKTKHY
  QKVPLKEPVTPVAAKIIPATRKKASLELELPSSPDSTGGTPKATISDTNDALQKNSNPYI
  TPNNRYGHQNGASYAWHFEARKSQILKCMECGSSHDTLQELTAHMMVTGHFIKVTNSAMK
  KGKPIVETPVTPTITTLLDEKVQSVPLAATTFTSPSNTPASISPKLNVEVKKEVDKEKAV
  TDEKPKQKDKPGEEEEKCDISSKYHYLTENDLEESPKGGLDILKSLENTVTSAINKAQNG
  TPSWGGYPSIHAAYQLPNMMKLSLGSSGKSTPLKPMFGNSEIVSPTKNQTLVSPPSSQTS
  PMPKTNFHAMEELVKKVTEKVAKVEEKMKEPDGKLSPPKRATPSPCSSEVGEPIKMEASS
  DGGFRSQENSPSPPRDGCKDGSPLAEPVENGKELVKPLASSLSGSTAIITDHPPEQPFVN
  PLSALQSVMNIHLGKAAKPSLPALDPMSMLFKMSNSLAEKAAVATPPPLQSKKADHLDRY
  FYHVNNDQPIDLTKGKSDKGCSLGSVLLSPTSTAPATSSSTVTTAKTSAVVSFMSNSPLR
  ENALSDISDMLKNLTESHTSKSSTPSSISEKSDIDGATLEEAEESTPAQKRKGRQSNWNP
  QHLLILQAQFAASLRQTSEGKYIMSDLSPQERMHISRFTGLSMTTISHWLANVKYQLRRT
  GGTKFLKNLDTGHPVFFCNDCASQIRTPSTYISHLESHLGFRLRDLSKLSTEQINSQIAQ
  TKSPSEKMVTSSPEEDLGTSYQCKLCNRTFASKHAVKLHLSKTHGKSPEDHLLYVSELEK
  Q
• Function: Transcriptional regulator involved in developmental processes. Functions in association with APBB1, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4. TSHZ3-mediated transcription repression involves the recruitment of histone deacetylases HDAC1 and HDAC2. Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s). Regulates the development of neurons involved in both respiratory rhythm and airflow control. Promotes maintenance of nucleus ambiguus (nA) motoneurons, which govern upper airway function, and establishes a respiratory rhythm generator (RRG) activity compatible with survival at birth. Involved in the differentiation of the proximal uretic smooth muscle cells during developmental processes. Involved in the up-regulation of myocardin, that directs the expression of smooth muscle cells in the proximal ureter. Involved in the modulation of glutamatergic synaptic transmission and long-term synaptic potentiation.
• Tissue Specificity: Expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease . Expressed in the fetal neocortex .

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[4]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[4]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[8]
Prostate cancer	DISF190Y	Strong	Posttranslational Modification	[4]
Prostate carcinoma	DISMJPLE	Strong	Posttranslational Modification	[4]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[8]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[9]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Limited	Autosomal dominant	[9]

2 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 Teashirt homolog 3 (TSHZ3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Teashirt homolog 3 (TSHZ3).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Teashirt homolog 3 (TSHZ3).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Teashirt homolog 3 (TSHZ3).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Teashirt homolog 3 (TSHZ3).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Teashirt homolog 3 (TSHZ3).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Teashirt homolog 3 (TSHZ3).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Teashirt homolog 3 (TSHZ3).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Teashirt homolog 3 (TSHZ3).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Teashirt homolog 3 (TSHZ3).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Teashirt homolog 3 (TSHZ3).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Teashirt homolog 3 (TSHZ3).	[21]

References

• [1] LH, progesterone, and TSH can stimulate aldosterone in vitro: a study on normal adrenal cortex and aldosterone producing adenoma.Horm Metab Res. 2014 May;46(5):318-21. doi: 10.1055/s-0033-1358733. Epub 2013 Dec 2.
• [2] MiR-338-5p Promotes Glioma Cell Invasion by Regulating TSHZ3 and MMP2.Cell Mol Neurobiol. 2018 Apr;38(3):669-677. doi: 10.1007/s10571-017-0525-x. Epub 2017 Aug 5.
• [3] TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.Nat Genet. 2016 Nov;48(11):1359-1369. doi: 10.1038/ng.3681. Epub 2016 Sep 26.
• [4] Rare and frequent promoter methylation, respectively, of TSHZ2 and 3 genes that are both downregulated in expression in breast and prostate cancers.PLoS One. 2011 Mar 14;6(3):e17149. doi: 10.1371/journal.pone.0017149.
• [5] A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.
• [6] MicroRNA-125b-1-3p mediates intervertebral disc degeneration in rats by targeting teashirt zinc finger homeobox 3.Exp Ther Med. 2018 Mar;15(3):2627-2633. doi: 10.3892/etm.2018.5715. Epub 2018 Jan 8.
• [7] Genome-Wide Assessment for RestingHeart Rate and Shared Genetics WithCardiometabolic Traits and Type 2 Diabetes.J Am Coll Cardiol. 2019 Oct 29;74(17):2162-2174. doi: 10.1016/j.jacc.2019.08.1055.
• [8] Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior.Biol Psychiatry. 2019 Aug 15;86(4):274-285. doi: 10.1016/j.biopsych.2019.03.974. Epub 2019 Mar 28.
• [9] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [10] 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.
• [11] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.