Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN4IPVV)

• DOT Name: Heart- and neural crest derivatives-expressed protein 1 (HAND1)
• Synonyms: Class A basic helix-loop-helix protein 27; bHLHa27; Extraembryonic tissues, heart, autonomic nervous system and neural crest derivatives-expressed protein 1; eHAND
• Gene Name: HAND1
• Related Disease:
  Cardiac disease
  Cardiac failure
  Colon cancer
  Colon carcinoma
  Colorectal neoplasm
  Congestive heart failure
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Gastric cancer
  Heart septal defect
  Huntington disease
  Hypoplastic left heart syndrome
  Hypoplastic left heart syndrome 1
  Stomach cancer
  Ventricular septal defect
  Advanced cancer
  Congenital heart disease
  Gastrointestinal stromal tumour
  Medulloblastoma
  Neoplasm
  Arrhythmia
  Cardiomyopathy
• UniProt ID: HAND1_HUMAN
• Pfam ID: PF00010
• Sequence:
  MNLVGSYAHHHHHHHPHPAHPMLHEPFLFGPASRCHQERPYFQSWLLSPADAAPDFPAGG
  PPPAAAAAATAYGPDARPGQSPGRLEALGGRLGRRKGSGPKKERRRTESINSAFAELREC
  IPNVPADTKLSKIKTLRLATSYIAYLMDVLAKDAQSGDPEAFKAELKKADGGRESKRKRE
  LQQHEGFPPALGPVEKRIKGRTGWPQQVWALELNQ
• Function: Transcription factor that plays an essential role in both trophoblast giant cell differentiation and in cardiac morphogenesis. Binds the DNA sequence 5'-NRTCTG-3' (non-canonical E-box). Acts as a transcriptional repressor of SOX15. In the adult, could be required for ongoing expression of cardiac-specific genes.
• Tissue Specificity: Heart.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: Cardiogenesis (R-HSA-9733709)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac disease	DISVO1I5	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Posttranslational Modification	[3]
Colon carcinoma	DISJYKUO	Strong	Posttranslational Modification	[3]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[3]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[2]
Dilated cardiomyopathy	DISX608J	Strong	Genetic Variation	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Heart septal defect	DISQ5C5J	Strong	Genetic Variation	[2]
Huntington disease	DISQPLA4	Strong	Altered Expression	[6]
Hypoplastic left heart syndrome	DISSLFZ4	Strong	Genetic Variation	[7]
Hypoplastic left heart syndrome 1	DISW3OY8	Strong	Genetic Variation	[7]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[8]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Congenital heart disease	DISQBA23	Moderate	Autosomal dominant	[10]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[11]
Medulloblastoma	DISZD2ZL	moderate	Altered Expression	[9]
Neoplasm	DISZKGEW	moderate	Biomarker	[9]
Arrhythmia	DISFF2NI	Limited	Biomarker	[12]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[13]

8 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 Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[15]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[16]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[21]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[22]

1 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 decreases the methylation of Heart- and neural crest derivatives-expressed protein 1 (HAND1).	[19]

References

• [1] Ontogeny of cardiac sympathetic innervation and its implications for cardiac disease.Pediatr Cardiol. 2012 Aug;33(6):923-8. doi: 10.1007/s00246-012-0248-1. Epub 2012 Mar 3.
• [2] HAND1 loss-of-function within the embryonic myocardium reveals survivable congenital cardiac defects and adult heart failure.Cardiovasc Res. 2020 Mar 1;116(3):605-618. doi: 10.1093/cvr/cvz182.
• [3] Integrative epigenome analysis identifies a Polycomb-targeted differentiation program as a tumor-suppressor event epigenetically inactivated in colorectal cancer.Cell Death Dis. 2014 Jul 17;5(7):e1324. doi: 10.1038/cddis.2014.283.
• [4] HAND2 loss-of-function mutation causes familial dilated cardiomyopathy. Eur J Med Genet. 2019 Sep;62(9):103540. doi: 10.1016/j.ejmg.2018.09.007. Epub 2018 Sep 12.
• [5] Accumulation of DNA methylation is associated with tumor stage in gastric cancer.Cancer. 2006 Mar 15;106(6):1250-9. doi: 10.1002/cncr.21754.
• [6] Transcriptomics of maternal and fetal membranes can discriminate between gestational-age matched preterm neonates with and without cognitive impairment diagnosed at 18-24 months.PLoS One. 2015 Mar 30;10(3):e0118573. doi: 10.1371/journal.pone.0118573. eCollection 2015.
• [7] The HAND1 frameshift A126FS mutation does not cause hypoplastic left heart syndrome in mice.Cardiovasc Res. 2017 Dec 1;113(14):1732-1742. doi: 10.1093/cvr/cvx166.
• [8] HAND1 loss-of-function mutation contributes to congenital double outlet right ventricle.Int J Mol Med. 2017 Mar;39(3):711-718. doi: 10.3892/ijmm.2017.2865. Epub 2017 Jan 20.
• [9] Nuclear translocation of Hand-1 acts as a molecular switch to regulate vascular radiosensitivity in medulloblastoma tumors: the protein uPAR is a cytoplasmic sequestration factor for Hand-1.Mol Cancer Ther. 2014 May;13(5):1309-22. doi: 10.1158/1535-7163.MCT-13-0892. Epub 2014 Mar 12.
• [10] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [11] Gastrointestinal stromal tumor enhancers support a transcription factor network predictive of clinical outcome.Proc Natl Acad Sci U S A. 2018 Jun 19;115(25):E5746-E5755. doi: 10.1073/pnas.1802079115. Epub 2018 Jun 4.
• [12] Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice.J Mol Cell Cardiol. 2009 Jul;47(1):133-41. doi: 10.1016/j.yjmcc.2009.04.007. Epub 2009 Apr 17.
• [13] Human eHAND, but not dHAND, is down-regulated in cardiomyopathies.J Mol Cell Cardiol. 2001 Sep;33(9):1607-14. doi: 10.1006/jmcc.2001.1434.
• [14] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [15] 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.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [18] 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.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.