Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFXF349)

• DOT Name: TSC22 domain family protein 2 (TSC22D2)
• Synonyms: TSC22-related-inducible leucine zipper protein 4
• Gene Name: TSC22D2
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Moyamoya disease
• UniProt ID: T22D2_HUMAN
• Pfam ID: PF01166
• Sequence:
  MSKMPAKKKSCFQITSVTTAQVATSITEDTESLDDPDESRTEDVSSEIFDVSRATDYGPE
  EVCERSSSEETLNNVGDAETPGTVSPNLLLDGQLAAAAAAPANGGGVVSARSVSGALAST
  LAAAATSAPAPGAPGGPQLAGSSAGPVTAAPSQPPTTCSSRFRVIKLDHGSGEPYRRGRW
  TCMEYYERDSDSSVLTRSGDCIRHSSTFDQTAERDSGLGATGGSVVVVVASMQGAHGPES
  GTDSSLTAVSQLPPSEKMSQPTPAQPQSFSVGQPQPPPPPVGGAVAQSSAPLPPFPGAAT
  GPQPMMAAAQPSQPQGAGPGGQTLPPTNVTLAQPAMSLPPQPGPAVGAPAAQQPQQFAYP
  QPQIPPGHLLPVQPSGQSEYLQQHVAGLQPPSPAQPSSTGAAASPATAATLPVGTGQNAS
  SVGAQLMGASSQPSEAMAPRTGPAQGGQVAPCQPTGVPPATVGGVVQPCLGPAGAGQPQS
  VPPPQMGGSGPLSAVPGGPHAVVPGVPNVPAAVPAPSVPSVSTTSVTMPNVPAPLAQSQQ
  LSSHTPVSRSSSIIQHVGLPLAPGTHSAPTSLPQSDLSQFQTQTQPLVGQVDDTRRKSEP
  LPQPPLSLIAENKPVVKPPVADSLANPLQLTPMNSLATSVFSIAIPVDGDEDRNPSTAFY
  QAFHLNTLKESKSLWDSASGGGVVAIDNKIEQAMDLVKSHLMYAVREEVEVLKEQIKELV
  ERNSLLERENALLKSLSSNDQLSQLPTQQANPGSTSQQQAVIAQPPQPTQPPQQPNVSSA
• Function: Reduces the level of nuclear PKM isoform M2 which results in repression of cyclin CCND1 transcription and reduced cell growth.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Moyamoya disease	DISO62CA	moderate	Genetic Variation	[2]

4 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 TSC22 domain family protein 2 (TSC22D2).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of TSC22 domain family protein 2 (TSC22D2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of TSC22 domain family protein 2 (TSC22D2).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of TSC22 domain family protein 2 (TSC22D2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TSC22 domain family protein 2 (TSC22D2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of TSC22 domain family protein 2 (TSC22D2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TSC22 domain family protein 2 (TSC22D2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of TSC22 domain family protein 2 (TSC22D2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TSC22 domain family protein 2 (TSC22D2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of TSC22 domain family protein 2 (TSC22D2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TSC22 domain family protein 2 (TSC22D2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of TSC22 domain family protein 2 (TSC22D2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of TSC22 domain family protein 2 (TSC22D2).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of TSC22 domain family protein 2 (TSC22D2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TSC22 domain family protein 2 (TSC22D2).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of TSC22 domain family protein 2 (TSC22D2).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of TSC22 domain family protein 2 (TSC22D2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of TSC22 domain family protein 2 (TSC22D2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of TSC22 domain family protein 2 (TSC22D2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TSC22 domain family protein 2 (TSC22D2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of TSC22 domain family protein 2 (TSC22D2).	[21]

References

• [1] TSC22D2 interacts with PKM2 and inhibits cell growth in colorectal cancer.Int J Oncol. 2016 Sep;49(3):1046-56. doi: 10.3892/ijo.2016.3599. Epub 2016 Jul 4.
• [2] Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study.Stroke. 2018 Jan;49(1):11-18. doi: 10.1161/STROKEAHA.117.017430.
• [3] 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.
• [4] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion. J Biomed Res. 2020 Jun 30;34(5):369-378. doi: 10.7555/JBR.34.20200013.
• [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.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.