Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0IRYG1)

• DOT Name: Suppressor of fused homolog (SUFU)
• Synonyms: SUFUH
• Gene Name: SUFU
• Related Disease:
  Acrocallosal syndrome
  Bacteremia
  Basal cell nevus syndrome
  Medulloblastoma
  Neural tube defect
  Advanced cancer
  Brain neoplasm
  Colon cancer
  Colon carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Gastrointestinal stromal tumour
  Hamartoma
  Joubert syndrome 32
  Malignant mesothelioma
  Matthew-Wood syndrome
  Neoplasm
  Ocular motor apraxia, Cogan type
  Osteoporosis
  Overactive bladder
  Split hand-foot malformation 3
  Acute graft versus host disease
  Carcinoma
  Gastric cancer
  Graft-versus-host disease
  Hirschsprung disease
  Inflammatory bowel disease
  Joubert syndrome
  Rhabdomyosarcoma
  Stomach cancer
  Oculodentodigital dysplasia
  Apraxia
  Ciliopathy
  Hereditary hemochromatosis
  Meningioma
  Patent ductus arteriosus
  Schizophrenia
• UniProt ID: SUFU_HUMAN
• PDB ID: 1M1L; 4BL8; 4BL9; 4BLA; 4BLB; 4BLD; 4KM8; 4KM9; 4KMD; 4KMH
• Pfam ID: PF05076 ; PF12470
• Sequence:
  MAELRPSGAPGPTAPPAPGPTAPPAFASLFPPGLHAIYGECRRLYPDQPNPLQVTAIVKY
  WLGGPDPLDYVSMYRNVGSPSANIPEHWHYISFGLSDLYGDNRVHEFTGTDGPSGFGFEL
  TFRLKRETGESAPPTWPAELMQGLARYVFQSENTFCSGDHVSWHSPLDNSESRIQHMLLT
  EDPQMQPVQTPFGVVTFLQIVGVCTEELHSAQQWNGQGILELLRTVPIAGGPWLITDMRR
  GETIFEIDPHLQERVDKGIETDGSNLSGVSAKCAWDDLSRPPEDDEDSRSICIGTQPRRL
  SGKDTEQIRETLRRGLEINSKPVLPPINPQRQNGLAHDRAPSRKDSLESDSSTAIIPHEL
  IRTRQLESVHLKFNQESGALIPLCLRGRLLHGRHFTYKSITGDMAITFVSTGVEGAFATE
  EHPYAAHGPWLQILLTEEFVEKMLEDLEDLTSPEEFKLPKEYSWPEKKLKVSILPDVVFD
  SPLH
• Function: Negative regulator in the hedgehog/smoothened signaling pathway. Down-regulates GLI1-mediated transactivation of target genes. Down-regulates GLI2-mediated transactivation of target genes. Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome. Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein. Negative regulator of beta-catenin signaling. Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full-length form of GLI3 (GLI3FL). GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A). Required for normal embryonic development. Required for the proper formation of hair follicles and the control of epidermal differentiation.
• Tissue Specificity: Ubiquitous in adult tissues. Detected in osteoblasts of the perichondrium in the developing limb of 12-week old embryos. Isoform 1 is detected in fetal brain, lung, kidney and testis. Isoform 2 is detected in fetal testis, and at much lower levels in fetal brain, lung and kidney.
• KEGG Pathway:
  Hedgehog sig.ling pathway (hsa04340)
  Pathways in cancer (hsa05200)
  Basal cell carcinoma (hsa05217)
• Reactome Pathway:
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)
  Hedgehog 'off' state (R-HSA-5610787)
  Hedgehog 'on' state (R-HSA-5632684)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acrocallosal syndrome	DISKMCG2	Definitive	GermlineCausalMutation	[1]
Bacteremia	DIS6N9RZ	Definitive	Genetic Variation	[2]
Basal cell nevus syndrome	DIST8BC2	Definitive	Autosomal dominant	[3]
Medulloblastoma	DISZD2ZL	Definitive	Autosomal dominant	[4]
Neural tube defect	DIS5J95E	Definitive	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[6]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[9]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[9]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[10]
Hamartoma	DIS0I87H	Strong	Biomarker	[11]
Joubert syndrome 32	DIS9170N	Strong	Autosomal recessive	[1]
Malignant mesothelioma	DISTHJGH	Strong	Genetic Variation	[12]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Ocular motor apraxia, Cogan type	DIS32GGL	Strong	Autosomal dominant	[15]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[16]
Overactive bladder	DISQR5TD	Strong	Biomarker	[17]
Split hand-foot malformation 3	DISIIYAQ	Strong	Altered Expression	[18]
Acute graft versus host disease	DIS8KLVM	moderate	Genetic Variation	[19]
Carcinoma	DISH9F1N	moderate	Altered Expression	[20]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[14]
Graft-versus-host disease	DIS0QADF	moderate	Genetic Variation	[19]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[21]
Inflammatory bowel disease	DISGN23E	moderate	Genetic Variation	[22]
Joubert syndrome	DIS7P5CO	Moderate	Autosomal dominant	[23]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[24]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[14]
Oculodentodigital dysplasia	DISSWR9C	Disputed	GermlineCausalMutation	[25]
Apraxia	DISULX63	Limited	Autosomal dominant	[23]
Ciliopathy	DIS10G4I	Limited	Autosomal recessive	[4]
Hereditary hemochromatosis	DISVG5MT	Limited	Altered Expression	[26]
Meningioma	DISPT4TG	Limited	Genetic Variation	[6]
Patent ductus arteriosus	DIS9P8YS	Limited	Biomarker	[27]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[28]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vismodegib	DM5IXKQ	Approved	Suppressor of fused homolog (SUFU) decreases the response to substance of Vismodegib.	[42]
LDE225	DMM9F25	Phase 2	Suppressor of fused homolog (SUFU) decreases the response to substance of LDE225.	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Suppressor of fused homolog (SUFU).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Suppressor of fused homolog (SUFU).	[30]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Suppressor of fused homolog (SUFU).	[31]
Marinol	DM70IK5	Approved	Marinol increases the expression of Suppressor of fused homolog (SUFU).	[34]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Suppressor of fused homolog (SUFU).	[35]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Suppressor of fused homolog (SUFU).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Suppressor of fused homolog (SUFU).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Suppressor of fused homolog (SUFU).	[39]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Suppressor of fused homolog (SUFU).	[40]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Suppressor of fused homolog (SUFU).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Suppressor of fused homolog (SUFU).	[32]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Suppressor of fused homolog (SUFU).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Suppressor of fused homolog (SUFU).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Suppressor of fused homolog (SUFU).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Suppressor of fused homolog (SUFU).	[33]

References

• [1] Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects. Am J Hum Genet. 2017 Oct 5;101(4):552-563. doi: 10.1016/j.ajhg.2017.08.017. Epub 2017 Sep 28.
• [2] Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea bacteremia.Infect Genet Evol. 2013 Jun;16:386-91. doi: 10.1016/j.meegid.2013.03.025. Epub 2013 Mar 26.
• [3] Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am J Med Genet A. 2009 Jul;149A(7):1539-43. doi: 10.1002/ajmg.a.32944.
• [4] 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.
• [5] An association study between SUFU gene polymorphisms and neural tube defects.Int J Neurosci. 2014 Jun;124(6):436-42. doi: 10.3109/00207454.2013.849249. Epub 2013 Nov 7.
• [6] Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis.Neuro Oncol. 2018 Jul 5;20(8):1122-1132. doi: 10.1093/neuonc/nox228.
• [7] Medulloblastoma: a problem of developmental biology.Cancer Cell. 2002 Jul;2(1):7-8. doi: 10.1016/s1535-6108(02)00090-9.
• [8] Aberrant expression of sonic hedgehog pathway in colon cancer and melanosis coli.J Dig Dis. 2013 Aug;14(8):417-24. doi: 10.1111/1751-2980.12060.
• [9] Nomegestrol Acetate Suppresses Human Endometrial Cancer RL95-2 Cells Proliferation In Vitro and In Vivo Possibly Related to Upregulating Expression of SUFU and Wnt7a.Int J Mol Sci. 2017 Jun 22;18(7):1337. doi: 10.3390/ijms18071337.
• [10] 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.
• [11] Multiple skin hamartomata: a possible novel clinical presentation of SUFU neoplasia syndrome.Fam Cancer. 2015 Mar;14(1):151-5. doi: 10.1007/s10689-014-9752-1.
• [12] Mutational analysis of hedgehog signaling pathway genes in human malignant mesothelioma.PLoS One. 2013 Jun 24;8(6):e66685. doi: 10.1371/journal.pone.0066685. Print 2013.
• [13] Identification of a novel alternative splicing transcript variant of the suppressor of fused: Relationship with lymph node metastasis in pancreatic ductal adenocarcinoma.Int J Oncol. 2016 Dec;49(6):2611-2619. doi: 10.3892/ijo.2016.3753. Epub 2016 Nov 3.
• [14] MiRNA-194 activates the Wnt/-catenin signaling pathway in gastric cancer by targeting the negative Wnt regulator, SUFU.Cancer Lett. 2017 Jan 28;385:117-127. doi: 10.1016/j.canlet.2016.10.035. Epub 2016 Oct 31.
• [15] Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia. Genet Med. 2021 Feb;23(2):341-351. doi: 10.1038/s41436-020-00979-w. Epub 2020 Oct 7.
• [16] MicroRNA-874 targeting SUFU involves in osteoblast proliferation and differentiation in osteoporosis rats through the Hedgehog signaling pathway.Biochem Biophys Res Commun. 2018 Nov 17;506(1):194-203. doi: 10.1016/j.bbrc.2018.09.187. Epub 2018 Oct 17.
• [17] Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline Amendment 2019.J Urol. 2019 Sep;202(3):558-563. doi: 10.1097/JU.0000000000000309. Epub 2019 Aug 8.
• [18] Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region.Am J Med Genet A. 2006 Jul 1;140(13):1384-95. doi: 10.1002/ajmg.a.31247.
• [19] Genome-wide single-nucleotide polymorphism analysis revealed SUFU suppression of acute graft-versus-host disease through downregulation of HLA-DR expression in recipient dendritic cells.Sci Rep. 2015 Jun 11;5:11098. doi: 10.1038/srep11098.
• [20] Non-canonical Hedgehog signaling activation in ovarian borderline tumors and ovarian carcinomas.Int J Oncol. 2017 Dec;51(6):1869-1877. doi: 10.3892/ijo.2017.4156. Epub 2017 Oct 12.
• [21] Identification of GLI Mutations in Patients With Hirschsprung Disease That Disrupt Enteric Nervous System Development in Mice.Gastroenterology. 2015 Dec;149(7):1837-1848.e5. doi: 10.1053/j.gastro.2015.07.060. Epub 2015 Aug 7.
• [22] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [23] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [24] Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development.J Pathol. 2006 Jan;208(1):17-25. doi: 10.1002/path.1882.
• [25] Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol. 2014 Dec 20;32(36):4155-61. doi: 10.1200/JCO.2014.58.2569. Epub 2014 Nov 17.
• [26] Loss of SUFU function in familial multiple meningioma.Am J Hum Genet. 2012 Sep 7;91(3):520-6. doi: 10.1016/j.ajhg.2012.07.015.
• [27] Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1-SUFU Interaction in PDA Cells.Front Pharmacol. 2017 Nov 16;8:820. doi: 10.3389/fphar.2017.00820. eCollection 2017.
• [28] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
• [29] 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.
• [30] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [31] Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin. J Soc Gynecol Investig. 2005 Oct;12(7):e55-67.
• [32] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [33] 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.
• [34] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [35] Down-regulation of Sonic hedgehog signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells. Acta Biochim Biophys Sin (Shanghai). 2008 Sep;40(9):819-29.
• [36] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [37] 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.
• [38] An integrative transcriptomic analysis reveals bisphenol A exposure-induced dysregulation of microRNA expression in human endometrial cells. Toxicol In Vitro. 2017 Jun;41:133-142. doi: 10.1016/j.tiv.2017.02.012. Epub 2017 Feb 24.
• [39] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [40] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [41] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.
• [42] Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 2014 Jul;20(7):732-40. doi: 10.1038/nm.3613. Epub 2014 Jun 29.