Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYH4BDG)

• DOT Name: Twist-related protein 2
• Synonyms: Class A basic helix-loop-helix protein 39; bHLHa39; Dermis-expressed protein 1; Dermo-1
• Gene Name: TWIST2
• Related Disease:
  Ablepharon macrostomia syndrome
  Barber-Say syndrome
  Focal facial dermal dysplasia type III
• UniProt ID: TWST2_HUMAN
• Pfam ID: PF00010
• Sequence:
  MEEGSSSPVSPVDSLGTSEEELERQPKRFGRKRRYSKKSSEDGSPTPGKRGKKGSPSAQS
  FEELQSQRILANVRERQRTQSLNEAFAALRKIIPTLPSDKLSKIQTLKLAARYIDFLYQV
  LQSDEMDNKMTSCSYVAHERLSYAFSVWRMEGAWSMSASH
• Function: Binds to the E-box consensus sequence 5'-CANNTG-3' as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C. Also represses expression of pro-inflammatory cytokines such as TNFA and IL1B. Involved in postnatal glycogen storage and energy metabolism. Inhibits the premature or ectopic differentiation of preosteoblast cells during osteogenesis, possibly by changing the internal signal transduction response of osteoblasts to external growth factors.
• Tissue Specificity: In the embryo, highly expressed in chondrogenic cells. In embryonic skin, expressed in the undifferentiated mesenchymal layer beneath the epidermis which later develops into the dermis. Expressed in early myeloid cells but not in lymphoid cells in the liver. Expression also detected in the secretory ependymal epithelium of the choroid plexus primordium. In the adult, expressed in secreting glandular tissues and tubules.
• KEGG Pathway: Proteoglycans in cancer (hsa05205)
• Reactome Pathway: Transcriptional regulation by RUNX2 (R-HSA-8878166)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ablepharon macrostomia syndrome	DIS1P3YX	Definitive	Autosomal dominant	[1]
Barber-Say syndrome	DISW5MTJ	Strong	Autosomal dominant	[1]
Focal facial dermal dysplasia type III	DISUJZH1	Strong	Autosomal recessive	[2]

6 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 2.	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Twist-related protein 2.	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Twist-related protein 2.	[5]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Twist-related protein 2.	[6]
GSK2816126	DMJDVW4	Phase 1	GSK2816126 decreases the expression of Twist-related protein 2.	[8]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Twist-related protein 2.	[10]

2 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 increases the methylation of Twist-related protein 2.	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Twist-related protein 2.	[9]

References

• [1] Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. Am J Hum Genet. 2015 Jul 2;97(1):99-110. doi: 10.1016/j.ajhg.2015.05.017. Epub 2015 Jun 25.
• [2] Setleis syndrome in Mexican-Nahua sibs due to a homozygous TWIST2 frameshift mutation and partial expression in heterozygotes: review of the focal facial dermal dysplasias and subtype reclassification. J Med Genet. 2011 Oct;48(10):716-20. doi: 10.1136/jmedgenet-2011-100251.
• [3] 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.
• [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] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [6] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [7] 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.
• [8] Epigenetic control of skeletal development by the histone methyltransferase Ezh2. J Biol Chem. 2015 Nov 13;290(46):27604-17.
• [9] 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.
• [10] 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.