Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1DWGXC)

DOT Name	Indian hedgehog protein (IHH)
Synonyms	IHH; EC 3.1.-.-; HHG-2
Gene Name	IHH
Related Disease	Acrocapitofemoral dysplasia ( ) Brachydactyly type A1 ( ) Adenocarcinoma ( ) Adenoma ( ) Biliary tract cancer ( ) Bone disease ( ) Brachydactyly ( ) Chondrosarcoma ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Craniosynostosis ( ) Endometriosis ( ) Ewing sarcoma ( ) Familial adenomatous polyposis ( ) Gastric cancer ( ) Gastrointestinal stromal tumour ( ) Hepatocellular carcinoma ( ) Hirschsprung disease ( ) Hypogonadotropic hypogonadism 7 with or without anosmia ( ) Kallmann syndrome ( ) Lung squamous cell carcinoma ( ) Metachondromatosis ( ) Neoplasm ( ) Osteoarthritis ( ) Pancreatic tumour ( ) Short stature with nonspecific skeletal abnormalities ( ) Squamous cell carcinoma ( ) Stomach cancer ( ) Thyroid gland papillary carcinoma ( ) Autosomal dominant prognathism ( ) Nephrocalcinosis ( ) Colorectal adenoma ( ) Congenital heart disease ( ) Fetal growth restriction ( )
UniProt ID	IHH_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	3K7G; 3K7H; 3K7I; 3K7J; 3N1F; 3N1M; 3N1O; 3N1P
EC Number	3.1.-.-
Pfam ID	PF01085 ; PF01079
Sequence	MSPARLRPRLHFCLVLLLLLVVPAAWGCGPGRVVGSRRRPPRKLVPLAYKQFSPNVPEKT LGASGRYEGKIARSSERFKELTPNYNPDIIFKDEENTGADRLMTQRCKDRLNSLAISVMN QWPGVKLRVTEGWDEDGHHSEESLHYEGRAVDITTSDRDRNKYGLLARLAVEAGFDWVYY ESKAHVHCSVKSEHSAAAKTGGCFPAGAQVRLESGARVALSAVRPGDRVLAMGEDGSPTF SDVLIFLDREPHRLRAFQVIETQDPPRRLALTPAHLLFTADNHTEPAARFRATFASHVQP GQYVLVAGVPGLQPARVAAVSTHVALGAYAPLTKHGTLVVEDVVASCFAAVADHHLAQLA FWPLRLFHSLAWGSWTPGEGVHWYPQLLYRLGRLLLEEGSFHPLGMSGAGS
Function	[Indian hedgehog protein]: The C-terminal part of the indian hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein into two parts followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product. Both activities occur in the reticulum endoplasmic. Plays a role in hedgehog paracrine signaling. Associated with the very-low-density lipoprotein (VLDL) particles to function as a circulating morphogen for endothelial cell integrity maintenance ; [Indian hedgehog protein N-product]: The dually lipidated indian hedgehog protein N-product is a morphogen which is essential for a variety of patterning events during development. Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. Plays a role in morphogenesis of the skeleton by coordinating growth and differentiation of the endochondral skeleton. Positively regulates PTHLH expression during endochondral bone formation preventing chondrocyte hypertrophy. In contrast, participates in normal chondrocyte proliferation in a PTHLH-independent pathway.
Tissue Specificity	Expressed in embryonic lung, and in adult kidney and liver.
KEGG Pathway	Hedgehog sig.ling pathway (hsa04340 ) Proteoglycans in cancer (hsa05205 )
Reactome Pathway	Hedgehog ligand biogenesis (R-HSA-5358346 ) Release of Hh-Np from the secreting cell (R-HSA-5362798 ) Ligand-receptor interactions (R-HSA-5632681 ) Hedgehog 'on' state (R-HSA-5632684 ) Activation of SMO (R-HSA-5635838 ) HHAT G278V doesn't palmitoylate Hh-Np (R-HSA-5658034 ) RUNX2 regulates chondrocyte maturation (R-HSA-8941284 ) Formation of lateral plate mesoderm (R-HSA-9758920 ) Class B/2 (Secretin family receptors) (R-HSA-373080 )

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acrocapitofemoral dysplasia	DISTY3WW	Definitive	Autosomal recessive	[1]
Brachydactyly type A1	DISZUO15	Definitive	Autosomal dominant	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Adenoma	DIS78ZEV	Strong	Altered Expression	[4]
Biliary tract cancer	DISBNYQL	Strong	Biomarker	[5]
Bone disease	DISE1F82	Strong	Biomarker	[6]
Brachydactyly	DIS2533F	Strong	Biomarker	[7]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Craniosynostosis	DIS6J405	Strong	Biomarker	[11]
Endometriosis	DISX1AG8	Strong	Biomarker	[12]
Ewing sarcoma	DISQYLV3	Strong	Altered Expression	[13]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[14]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
Hirschsprung disease	DISUUSM1	Strong	Biomarker	[17]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Strong	Genetic Variation	[18]
Kallmann syndrome	DISO3HDG	Strong	Genetic Variation	[19]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[3]
Metachondromatosis	DISUM6CO	Strong	Altered Expression	[20]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Osteoarthritis	DIS05URM	Strong	Biomarker	[21]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[22]
Short stature with nonspecific skeletal abnormalities	DISRNBJZ	Strong	Genetic Variation	[23]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[3]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[14]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[24]
Autosomal dominant prognathism	DIS2G3FF	moderate	Altered Expression	[25]
Nephrocalcinosis	DIS5ZVJP	moderate	Biomarker	[26]
Colorectal adenoma	DISTSVHM	Limited	Biomarker	[27]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[28]
Fetal growth restriction	DIS5WEJ5	Limited	Genetic Variation	[29]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Indian hedgehog protein (IHH).	[30]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Indian hedgehog protein (IHH).	[32]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Indian hedgehog protein (IHH).	[33]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Indian hedgehog protein (IHH).	[30]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Indian hedgehog protein (IHH).	[35]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of Indian hedgehog protein (IHH).	[36]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Indian hedgehog protein (IHH).	[37]
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2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Indian hedgehog protein (IHH).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Indian hedgehog protein (IHH).	[34]
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References

1	Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am J Hum Genet. 2003 Apr;72(4):1040-6. doi: 10.1086/374318. Epub 2003 Mar 11.
2	A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family. J Hum Genet. 2006;51(8):727-731. doi: 10.1007/s10038-006-0012-6. Epub 2006 Jul 27.
3	WIF-1 and Ihh Expression and Clinical Significance in Patients With Lung Squamous Cell Carcinoma and Adenocarcinoma.Appl Immunohistochem Mol Morphol. 2018 Aug;26(7):454-461. doi: 10.1097/PAI.0000000000000449.
4	Stromal Indian hedgehog signaling is required for intestinal adenoma formation in mice.Gastroenterology. 2015 Jan;148(1):170-180.e6. doi: 10.1053/j.gastro.2014.10.006. Epub 2014 Oct 13.
5	Identification of the transforming activity of Indian hedgehog by retroviral expression screening.Cancer Sci. 2010 Jan;101(1):60-4. doi: 10.1111/j.1349-7006.2009.01355.x. Epub 2009 Sep 9.
6	Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells.Cancer Res. 2008 Oct 1;68(19):7795-802. doi: 10.1158/0008-5472.CAN-08-1078.
7	Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat. 2010 Oct;31(10):1155-62. doi: 10.1002/humu.21338.
8	Differential expression of runx2 and Indian hedgehog in cartilaginous tumors.Pathol Oncol Res. 2007;13(1):32-7. doi: 10.1007/BF02893438. Epub 2007 Mar 27.
9	Colorectal Cancer Metastases Settle in the Hepatic Microenvironment Through 51 Integrin.J Cell Biochem. 2015 Oct;116(10):2385-96. doi: 10.1002/jcb.25189.
10	Influence of components of tumour microenvironment on the response of HCT-116 colorectal cancer to the ruthenium-based drug NAMI-A.J Inorg Biochem. 2017 Mar;168:90-97. doi: 10.1016/j.jinorgbio.2016.11.031. Epub 2016 Dec 2.
11	Regulation of Calvarial Osteogenesis by Concomitant De-repression of GLI3 and Activation of IHH Targets.Front Physiol. 2017 Dec 19;8:1036. doi: 10.3389/fphys.2017.01036. eCollection 2017.
12	Molecular evidence for differences in endometrium in severe versus mild endometriosis.Reprod Sci. 2011 Mar;18(3):229-51. doi: 10.1177/1933719110386241. Epub 2010 Nov 9.
13	Investigation of IGF2, Hedgehog and fusion gene expression profiles in pediatric sarcomas.Growth Horm IGF Res. 2014 Aug;24(4):130-6. doi: 10.1016/j.ghir.2014.04.002. Epub 2014 Apr 16.
14	Hedgehog signaling pathway and gastric cancer.Cancer Biol Ther. 2005 Oct;4(10):1050-4. doi: 10.4161/cbt.4.10.2184. Epub 2005 Oct 18.
15	Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
16	Impairment of the Pin1/E2F1 axis in the anti-proliferative effect of bortezomib in hepatocellular carcinoma cells.Biochimie. 2015 May;112:85-95. doi: 10.1016/j.biochi.2015.02.015. Epub 2015 Mar 3.
17	Is there a role for the IHH gene in Hirschsprung's disease?.Neurogastroenterol Motil. 2003 Dec;15(6):663-8. doi: 10.1046/j.1350-1925.2003.00447.x.
18	Prevalence and associated phenotypes of PLXNA1 variants in normosmic and anosmic idiopathic hypogonadotropic hypogonadism.Clin Genet. 2019 Feb;95(2):320-324. doi: 10.1111/cge.13482. Epub 2018 Dec 26.
19	Clinical Case Seminar. Peculiar prolactinomas in patients with pituitary developmental gene mutations: from an adult endocrinologist perspective.Hormones (Athens). 2012 Apr-Jun;11(2):189-98. doi: 10.14310/horm.2002.1346.
20	EXT-related pathways are not involved in the pathogenesis of dysplasia epiphysealis hemimelica and metachondromatosis.J Pathol. 2006 Jul;209(3):411-9. doi: 10.1002/path.1985.
21	Correlation between Gene Expression and Osteoarthritis Progression in Human.Int J Mol Sci. 2016 Jul 14;17(7):1126. doi: 10.3390/ijms17071126.
22	Indian hedgehog signaling pathway: expression and regulation in pancreatic cancer.Int J Cancer. 2004 Jul 10;110(5):668-76. doi: 10.1002/ijc.20194.
23	IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy.J Clin Endocrinol Metab. 2018 Feb 1;103(2):604-614. doi: 10.1210/jc.2017-02026.
24	MYC promotes the development of papillary thyroid carcinoma by inhibiting the expression of lncRNA PAX8AS1:28.Oncol Rep. 2019 Apr;41(4):2511-2517. doi: 10.3892/or.2019.6996. Epub 2019 Feb 1.
25	Genes, genetics, and Class III malocclusion.Orthod Craniofac Res. 2010 May;13(2):69-74. doi: 10.1111/j.1601-6343.2010.01485.x.
26	CYP24A1 Mutation in a Girl Infant with Idiopathic Infantile Hypercalcemia.J Clin Res Pediatr Endocrinol. 2018 Mar 1;10(1):83-86. doi: 10.4274/jcrpe.4841. Epub 2017 Sep 6.
27	Opposite expression patterns of Sonic hedgehog and Indian hedgehog are associated with aberrant methylation status of their promoters in colorectal cancers.Pathology. 2010;42(6):553-9. doi: 10.3109/00313025.2010.508785.
28	A de novo 2q35-q36.1 deletion incorporating IHH in a Chinese boy (47,XYY) with syndactyly, type III Waardenburg syndrome, and congenital heart disease.Genet Mol Res. 2016 Dec 2;15(4). doi: 10.4238/gmr15049060.
29	Intrauterine growth restriction combined with a maternal high-fat diet increased adiposity and serum corticosterone levels in adult rat offspring.J Dev Orig Health Dis. 2018 Jun;9(3):315-328. doi: 10.1017/S2040174418000016. Epub 2018 Feb 5.
30	Effect of resveratrol on proliferation and apoptosis of human pancreatic cancer MIA PaCa-2 cells may?involve inhibition of the Hedgehog signaling pathway. Mol Med Rep. 2014 Nov;10(5):2563-7. doi: 10.3892/mmr.2014.2511. Epub 2014 Aug 21.
31	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.
32	Parathyroid hormone 1-34 reduces dexamethasone-induced terminal differentiation in human articular chondrocytes. Toxicology. 2016 Aug 10;368-369:116-128.
33	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
34	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.
35	Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
36	Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
37	Deguelin inhibits growth of breast cancer cells by modulating the expression of key members of the Wnt signaling pathway. Cancer Prev Res (Phila). 2009 Nov;2(11):942-50. doi: 10.1158/1940-6207.CAPR-08-0232. Epub 2009 Oct 27.