Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQA8BD4)

• DOT Name: SAM and SH3 domain-containing protein 1 (SASH1)
• Synonyms: Proline-glutamate repeat-containing protein
• Gene Name: SASH1
• Related Disease:
  Diabetic kidney disease
  Skin cancer
  Skin carcinoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Bone osteosarcoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Colonic neoplasm
  Dyschromatosis universalis hereditaria
  Esophageal squamous cell carcinoma
  Glioma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Osteosarcoma
  Triple negative breast cancer
  Acute myelogenous leukaemia
  Gastric cancer
  Stomach cancer
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Familial generalized lentiginosis
  Pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Colon cancer
  Colon carcinoma
  Dyschromatosis universalis hereditaria 1
  Hypopigmentation of the skin
  Liver cancer
  Noonan syndrome with multiple lentigines
• UniProt ID: SASH1_HUMAN
• PDB ID: 2DL0; 2EBP
• Pfam ID: PF00536 ; PF07647 ; PF07653 ; PF12485
• Sequence:
  MEDAGAAGPGPEPEPEPEPEPEPAPEPEPEPKPGAGTSEAFSRLWTDVMGILDGSLGNID
  DLAQQYADYYNTCFSDVCERMEELRKRRVSQDLEVEKPDASPTSLQLRSQIEESLGFCSA
  VSTPEVERKNPLHKSNSEDSSVGKGDWKKKNKYFWQNFRKNQKGIMRQTSKGEDVGYVAS
  EITMSDEERIQLMMMVKEKMITIEEALARLKEYEAQHRQSAALDPADWPDGSYPTFDGSS
  NCNSREQSDDETEESVKFKRLHKLVNSTRRVRKKLIRVEEMKKPSTEGGEEHVFENSPVL
  DERSALYSGVHKKPLFFDGSPEKPPEDDSDSLTTSPSSSSLDTWGAGRKLVKTFSKGESR
  GLIKPPKKMGTFFSYPEEEKAQKVSRSLTEGEMKKGLGSLSHGRTCSFGGFDLTNRSLHV
  GSNNSDPMGKEGDFVYKEVIKSPTASRISLGKKVKSVKETMRKRMSKKYSSSVSEQDSGL
  DGMPGSPPPSQPDPEHLDKPKLKAGGSVESLRSSLSGQSSMSGQTVSTTDSSTSNRESVK
  SEDGDDEEPPYRGPFCGRARVHTDFTPSPYDTDSLKLKKGDIIDIISKPPMGTWMGLLNN
  KVGTFKFIYVDVLSEDEEKPKRPTRRRRKGRPPQPKSVEDLLDRINLKEHMPTFLFNGYE
  DLDTFKLLEEEDLDELNIRDPEHRAVLLTAVELLQEYDSNSDQSGSQEKLLVDSQGLSGC
  SPRDSGCYESSENLENGKTRKASLLSAKSSTEPSLKSFSRNQLGNYPTLPLMKSGDALKQ
  GQEEGRLGGGLAPDTSKSCDPPGVTGLNKNRRSLPVSICRSCETLEGPQTVDTWPRSHSL
  DDLQVEPGAEQDVPTEVTEPPPQIVPEVPQKTTASSTKAQPLEQDSAVDNALLLTQSKRF
  SEPQKLTTKKLEGSIAASGRGLSPPQCLPRNYDAQPPGAKHGLARTPLEGHRKGHEFEGT
  HHPLGTKEGVDAEQRMQPKIPSQPPPVPAKKSRERLANGLHPVPMGPSGALPSPDAPCLP
  VKRGSPASPTSPSDCPPALAPRPLSGQAPGSPPSTRPPPWLSELPENTSLQEHGVKLGPA
  LTRKVSCARGVDLETLTENKLHAEGIDLTEEPYSDKHGRCGIPEALVQRYAEDLDQPERD
  VAANMDQIRVKQLRKQHRMAIPSGGLTEICRKPVSPGCISSVSDWLISIGLPMYAGTLST
  AGFSTLSQVPSLSHTCLQEAGITEERHIRKLLSAARLFKLPPGPEAM
• Function: Is a positive regulator of NF-kappa-B signaling downstream of TLR4 activation. It acts as a scaffold molecule to assemble a molecular complex that includes TRAF6, MAP3K7, CHUK and IKBKB, thereby facilitating NF-kappa-B signaling activation. Regulates TRAF6 and MAP3K7 ubiquitination. Involved in the regulation of cell mobility. Regulates lipolysaccharide (LPS)-induced endothelial cell migration. Is involved in the regulation of skin pigmentation through the control of melanocyte migration in the epidermis.
• Tissue Specificity: Expressed ubiquitously, with highest levels in lung, placenta, spleen and thymus. Down-regulated in the majority (74%) of breast tumors in comparison with corresponding normal breast epithelial tissues. Expressed in the epidermis, epidermal keratinocytes, dermal fibroblasts and melanocytes .

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic kidney disease	DISJMWEY	Definitive	Genetic Variation	[1]
Skin cancer	DISTM18U	Definitive	Genetic Variation	[2]
Skin carcinoma	DISUZREN	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Biomarker	[8]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[9]
Dyschromatosis universalis hereditaria	DIS5MQWA	Strong	Biomarker	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[13]
Lung carcinoma	DISTR26C	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[5]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[14]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[15]
Gastric cancer	DISXGOUK	moderate	Biomarker	[16]
Stomach cancer	DISKIJSX	moderate	Biomarker	[16]
Thyroid cancer	DIS3VLDH	moderate	Biomarker	[17]
Thyroid gland carcinoma	DISMNGZ0	moderate	Biomarker	[17]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[17]
Familial generalized lentiginosis	DIS9QHVD	Supportive	Autosomal dominant	[18]
Pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome	DISB983R	Supportive	Autosomal recessive	[2]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[19]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[19]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[12]
Colon cancer	DISVC52G	Limited	Biomarker	[20]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[20]
Dyschromatosis universalis hereditaria 1	DISMWXB8	Limited	Autosomal dominant	[21]
Hypopigmentation of the skin	DIS39YKC	Limited	Biomarker	[22]
Liver cancer	DISDE4BI	Limited	Altered Expression	[12]
Noonan syndrome with multiple lentigines	DIS014D0	Limited	Biomarker	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of SAM and SH3 domain-containing protein 1 (SASH1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of SAM and SH3 domain-containing protein 1 (SASH1).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[26]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[29]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[30]
Menadione	DMSJDTY	Approved	Menadione affects the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[32]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[33]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[40]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[41]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of SAM and SH3 domain-containing protein 1 (SASH1).	[42]

References

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• [2] Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma. Eur J Hum Genet. 2015 Jul;23(7):957-62. doi: 10.1038/ejhg.2014.213. Epub 2014 Oct 15.
• [3] MiR-130b promotes the progression of oesophageal squamous cell carcinoma by targeting SASH1.J Cell Mol Med. 2019 Jan;23(1):93-103. doi: 10.1111/jcmm.13887. Epub 2018 Nov 15.
• [4] SASH1, a new potential link between smoking and atherosclerosis.Atherosclerosis. 2015 Oct;242(2):571-9. doi: 10.1016/j.atherosclerosis.2015.08.013. Epub 2015 Aug 14.
• [5] Regulatory mechanism of microRNA-128 in osteosarcoma tumorigenesis and evolution through targeting SASH1.Oncol Lett. 2018 Jun;15(6):8687-8694. doi: 10.3892/ol.2018.8397. Epub 2018 Mar 30.
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• [22] Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination.Clin Genet. 2016 Oct;90(4):372-7. doi: 10.1111/cge.12728. Epub 2016 Feb 3.
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• [36] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [37] 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.
• [38] 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.
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