Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT29A838)

• DOT Name: E3 ubiquitin-protein ligase SIAH1 (SIAH1)
• Synonyms: EC 2.3.2.27; RING-type E3 ubiquitin transferase SIAH1; Seven in absentia homolog 1; Siah-1; Siah-1a
• Gene Name: SIAH1
• Related Disease:
  Hepatocellular carcinoma
  Neuroblastoma
  Adult glioblastoma
  Astrocytoma
  B-cell lymphoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Buratti-Harel syndrome
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Familial adenomatous polyposis
  Fatty liver disease
  Glioblastoma multiforme
  Glioma
  Hepatitis B virus infection
  Hyperaldosteronism
  Malignant glioma
  Melanoma
  Neoplasm
  Oropharyngeal cancer
  Oropharyngeal carcinoma
  Pancreatic tumour
  Primary aldosteronism
  Triple negative breast cancer
  Cervical carcinoma
  Complex neurodevelopmental disorder
  Gastric cancer
  Nasopharyngeal carcinoma
  Stomach cancer
  Gastric neoplasm
  Advanced cancer
  Prostate cancer
  Squamous cell carcinoma
• UniProt ID: SIAH1_HUMAN
• PDB ID: 2A25; 4C9Z; 4CA1; 4I7B; 4I7C; 4I7D; 4X3G; 5WZZ; 8HEO
• EC Number: 2.3.2.27
• Pfam ID: PF21362 ; PF03145 ; PF21361
• Sequence:
  MSRQTATALPTGTSKCPPSQRVPALTGTTASNNDLASLFECPVCFDYVLPPILQCQSGHL
  VCSNCRPKLTCCPTCRGPLGSIRNLAMEKVANSVLFPCKYASSGCEITLPHTEKADHEEL
  CEFRPYSCPCPGASCKWQGSLDAVMPHLMHQHKSITTLQGEDIVFLATDINLPGAVDWVM
  MQSCFGFHFMLVLEKQEKYDGHQQFFAIVQLIGTRKQAENFAYRLELNGHRRRLTWEATP
  RSIHEGIATAIMNSDCLVFDTSIAQLFAENGNLGINVTISMC
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes. Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (ELL2, MYB, POU2AF1, PML and RBBP8), a cell surface receptor (DCC), the cell-surface receptor-type tyrosine kinase FLT3, the cytoplasmic signal transduction molecules (KLF10/TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule motor protein (KIF22), a protein involved in synaptic vesicle function in neurons (SYP), a structural protein (CTNNB1) and SNCAIP. Confers constitutive instability to HIPK2 through proteasomal degradation. It is thereby involved in many cellular processes such as apoptosis, tumor suppression, cell cycle, axon guidance, transcription regulation, spermatogenesis and TNF-alpha signaling. Has some overlapping function with SIAH2. Induces apoptosis in cooperation with PEG3. Upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating the translocation of GAPDH to the nucleus. GAPDH acts as a stabilizer of SIAH1, facilitating the degradation of nuclear proteins. Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4. Also part of the Wnt signaling pathway in which it mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of AXIN1.
• Tissue Specificity: Widely expressed at a low level. Down-regulated in advanced hepatocellular carcinomas.
• KEGG Pathway:
  p53 sig.ling pathway (hsa04115)
  Ubiquitin mediated proteolysis (hsa04120)
  Mitophagy - animal (hsa04137)
  Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  Amyloid fiber formation (R-HSA-977225)
  Antigen processing (R-HSA-983168)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Astrocytoma	DISL3V18	Strong	Biomarker	[4]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Buratti-Harel syndrome	DISYU6FG	Strong	Autosomal dominant	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[11]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[12]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[14]
Hyperaldosteronism	DIS3WGAL	Strong	Biomarker	[15]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[13]
Melanoma	DIS1RRCY	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Oropharyngeal cancer	DISDAMTJ	Strong	Biomarker	[18]
Oropharyngeal carcinoma	DIS7K3AI	Strong	Biomarker	[18]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[19]
Primary aldosteronism	DISOEFNH	Strong	Genetic Variation	[15]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[20]
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal dominant	[21]
Gastric cancer	DISXGOUK	moderate	Biomarker	[22]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[23]
Stomach cancer	DISKIJSX	moderate	Biomarker	[22]
Gastric neoplasm	DISOKN4Y	Disputed	Genetic Variation	[24]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[25]
Prostate cancer	DISF190Y	Limited	Biomarker	[26]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[28]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[30]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[31]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[32]
Selenium	DM25CGV	Approved	Selenium decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[33]
Menadione	DMSJDTY	Approved	Menadione affects the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[32]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[34]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[35]
Reserpine	DM6VM38	Approved	Reserpine increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[36]
Hexachlorophene	DMLKSE0	Approved	Hexachlorophene increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[38]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[39]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[33]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[40]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[41]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[42]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[43]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[44]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of E3 ubiquitin-protein ligase SIAH1 (SIAH1).	[45]

References

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• [12] HIF-1 coordinates epigenetic activation of SIAH1 in hepatocytes in response to nutritional stress.Biochim Biophys Acta Gene Regul Mech. 2017 Oct;1860(10):1037-1046. doi: 10.1016/j.bbagrm.2017.08.002. Epub 2017 Aug 24.
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• [38] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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