Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB3H60O)

• DOT Name: Twist-related protein 1
• Synonyms: Class A basic helix-loop-helix protein 38; bHLHa38; H-twist
• Gene Name: TWIST1
• Related Disease:
  Saethre-Chotzen syndrome
  TWIST1-related craniosynostosis
  Obsolete isolated brachycephaly
  Obsolete isolated plagiocephaly
  Obsolete isolated scaphocephaly
  Sweeney-Cox syndrome
• UniProt ID: TWST1_HUMAN
• PDB ID: 2MJV
• Pfam ID: PF00010
• Sequence:
  MMQDVSSSPVSPADDSLSNSEEEPDRQQPPSGKRGGRKRRSSRRSAGGGAGPGGAAGGGV
  GGGDEPGSPAQGKRGKKSAGCGGGGGAGGGGGSSSGGGSPQSYEELQTQRVMANVRERQR
  TQSLNEAFAALRKIIPTLPSDKLSKIQTLKLAARYIDFLYQVLQSDELDSKMASCSYVAH
  ERLSYAFSVWRMEGAWSMSASH
• Function: Acts as a transcriptional regulator. Inhibits myogenesis by sequestrating E proteins, inhibiting trans-activation by MEF2, and inhibiting DNA-binding by MYOD1 through physical interaction. This interaction probably involves the basic domains of both proteins. Also represses expression of pro-inflammatory cytokines such as TNFA and IL1B. Regulates cranial suture patterning and fusion. Activates transcription as a heterodimer with E proteins. Regulates gene expression differentially, depending on dimer composition. Homodimers induce expression of FGFR2 and POSTN while heterodimers repress FGFR2 and POSTN expression and induce THBS1 expression. Heterodimerization is also required for osteoblast differentiation. Represses the activity of the circadian transcriptional activator: NPAS2-BMAL1 heterodimer.
• Tissue Specificity: Subset of mesodermal cells.
• KEGG Pathway: Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  Transcriptional regulation by RUNX2 (R-HSA-8878166)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Saethre-Chotzen syndrome	DIS3A437	Definitive	Autosomal dominant	[1]
TWIST1-related craniosynostosis	DISGRP2G	Definitive	Autosomal dominant	[2]
Obsolete isolated brachycephaly	DIS39ZDS	Supportive	Autosomal dominant	[2]
Obsolete isolated plagiocephaly	DISSZTKC	Supportive	Autosomal dominant	[2]
Obsolete isolated scaphocephaly	DISTSFJZ	Supportive	Autosomal dominant	[2]
Sweeney-Cox syndrome	DISRGXGU	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Twist-related protein 1 decreases the response to substance of Arsenic.	[30]
Gefitinib	DM15F0X	Approved	Twist-related protein 1 affects the response to substance of Gefitinib.	[31]
Crizotinib	DM4F29C	Approved	Twist-related protein 1 decreases the response to substance of Crizotinib.	[32]
Osimertinib	DMRJLAT	Approved	Twist-related protein 1 decreases the response to substance of Osimertinib.	[33]

27 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 Twist-related protein 1.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Twist-related protein 1.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Twist-related protein 1.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Twist-related protein 1.	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Twist-related protein 1.	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Twist-related protein 1.	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Twist-related protein 1.	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Twist-related protein 1.	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Twist-related protein 1.	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Twist-related protein 1.	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Twist-related protein 1.	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Twist-related protein 1.	[13]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Twist-related protein 1.	[14]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Twist-related protein 1.	[15]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Twist-related protein 1.	[16]
Ketamine	DMT5HA4	Approved	Ketamine increases the expression of Twist-related protein 1.	[17]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone decreases the expression of Twist-related protein 1.	[18]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Twist-related protein 1.	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Twist-related protein 1.	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Twist-related protein 1.	[21]
Piperlongumine	DMIZCOE	Preclinical	Piperlongumine decreases the expression of Twist-related protein 1.	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Twist-related protein 1.	[24]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Twist-related protein 1.	[25]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Twist-related protein 1.	[26]
Cordycepin	DM72Y01	Investigative	Cordycepin decreases the expression of Twist-related protein 1.	[27]
DIECKOL	DMBCK4G	Investigative	DIECKOL decreases the expression of Twist-related protein 1.	[28]
HONOKIOL	DMJWT3X	Investigative	HONOKIOL decreases the expression of Twist-related protein 1.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Twist-related protein 1.	[23]

References

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• [2] Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am J Med Genet A. 2007 Apr 1;143A(7):678-86. doi: 10.1002/ajmg.a.31630.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
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• [7] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
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• [10] 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.
• [11] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [14] Enhancement of cancer stem-like and epithelial-mesenchymal transdifferentiation property in oral epithelial cells with long-term nicotine exposure: reversal by targeting SNAIL. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):459-69.
• [15] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [16] In vitro antitumoral effects of the steroid ouabain on human thyroid papillary carcinoma cell lines. Environ Toxicol. 2021 Jul;36(7):1338-1348. doi: 10.1002/tox.23130. Epub 2021 Mar 24.
• [17] Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-1. Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F961-F972. doi: 10.1152/ajprenal.00686.2016. Epub 2017 Mar 22.
• [18] Inhibition of NF-B and metastasis in irinotecan (CPT-11)-resistant LoVo colon cancer cells by thymoquinone via JNK and p38. Environ Toxicol. 2017 Feb;32(2):669-678. doi: 10.1002/tox.22268. Epub 2016 Apr 5.
• [19] Histone acetylation-mediated regulation of the Hippo pathway. PLoS One. 2013 May 6;8(5):e62478. doi: 10.1371/journal.pone.0062478. Print 2013.
• [20] Benzo(a)pyrene promotes A549 cell migration and invasion through up-regulating Twist. Arch Toxicol. 2015 Mar;89(3):451-8. doi: 10.1007/s00204-014-1269-8. Epub 2014 May 22.
• [21] 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.
• [22] Piperlongumine induces ROS mediated apoptosis by transcriptional regulation of SMAD4/P21/P53 genes and synergizes with doxorubicin in osteosarcoma cells. Chem Biol Interact. 2022 Feb 25;354:109832. doi: 10.1016/j.cbi.2022.109832. Epub 2022 Jan 24.
• [23] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [24] 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.
• [25] Differences in glucose concentration shows new perspectives in gastric cancer metabolism. Toxicol In Vitro. 2022 Aug;82:105357. doi: 10.1016/j.tiv.2022.105357. Epub 2022 Apr 12.
• [26] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [27] Cordycepin Inhibits Triple-Negative Breast Cancer Cell Migration and Invasion by Regulating EMT-TFs SLUG, TWIST1, SNAIL1, and ZEB1. Front Oncol. 2022 Jun 14;12:898583. doi: 10.3389/fonc.2022.898583. eCollection 2022.
• [28] Dieckol inhibits non-small-cell lung cancer cell proliferation and migration by regulating the PI3K/AKT signaling pathway. J Biochem Mol Toxicol. 2019 Aug;33(8):e22346. doi: 10.1002/jbt.22346. Epub 2019 Jul 10.
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• [32] Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma. Cell Signal. 2012 Apr;24(4):852-8. doi: 10.1016/j.cellsig.2011.11.020. Epub 2011 Dec 8.
• [33] Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene. 2019 Jan;38(5):656-670. doi: 10.1038/s41388-018-0482-y. Epub 2018 Aug 31.