Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2O5ZBK)

• DOT Name: Suppressor of cytokine signaling 6 (SOCS6)
• Synonyms: SOCS-6; Cytokine-inducible SH2 protein 4; CIS-4; Suppressor of cytokine signaling 4; SOCS-4
• Gene Name: SOCS6
• Related Disease:
  Parkinsonian disorder
  Acute leukaemia
  Adult glioblastoma
  Advanced cancer
  Allergic rhinitis
  Bladder cancer
  Brain neoplasm
  Cervical cancer
  Cervical carcinoma
  Endometrial carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Lung squamous cell carcinoma
  Medium chain acyl-CoA dehydrogenase deficiency
  Medulloblastoma
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
  Primary myelofibrosis
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Nasopharyngeal carcinoma
  Bone osteosarcoma
  Kaposi sarcoma
  Osteosarcoma
  Colorectal carcinoma
  Periodontitis
• UniProt ID: SOCS6_HUMAN
• PDB ID: 2VIF
• Pfam ID: PF00017 ; PF07525
• Sequence:
  MKKISLKTLRKSFNLNKSKEETDFMVVQQPSLASDFGKDDSLFGSCYGKDMASCDINGED
  EKGGKNRSKSESLMGTLKRRLSAKQKSKGKAGTPSGSSADEDTFSSSSAPIVFKDVRAQR
  PIRSTSLRSHHYSPAPWPLRPTNSEETCIKMEVRVKALVHSSSPSPALNGVRKDFHDLQS
  ETTCQEQANSLKSSASHNGDLHLHLDEHVPVVIGLMPQDYIQYTVPLDEGMYPLEGSRSY
  CLDSSSPMEVSAVPPQVGGRAFPEDESQVDQDLVVAPEIFVDQSVNGLLIGTTGVMLQSP
  RAGHDDVPPLSPLLPPMQNNQIQRNFSGLTGTEAHVAESMRCHLNFDPNSAPGVARVYDS
  VQSSGPMVVTSLTEELKKLAKQGWYWGPITRWEAEGKLANVPDGSFLVRDSSDDRYLLSL
  SFRSHGKTLHTRIEHSNGRFSFYEQPDVEGHTSIVDLIEHSIRDSENGAFCYSRSRLPGS
  ATYPVRLTNPVSRFMQVRSLQYLCRFVIRQYTRIDLIQKLPLPNKMKDYLQEKHY
• Function: SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. May be a substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Regulates KIT degradation by ubiquitination of the tyrosine-phosphorylated receptor.
• KEGG Pathway:
  JAK-STAT sig.ling pathway (hsa04630)
  Prolactin sig.ling pathway (hsa04917)
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Negative regulation of FLT3 (R-HSA-9706369)
  Regulation of KIT signaling (R-HSA-1433559)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinsonian disorder	DISHGY45	Definitive	Biomarker	[1]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[7]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[8]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[8]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[12]
Medium chain acyl-CoA dehydrogenase deficiency	DISB8C4K	Strong	Biomarker	[13]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[15]
Pancreatic cancer	DISJC981	Strong	Biomarker	[16]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[17]
Prostate cancer	DISF190Y	Strong	Altered Expression	[4]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[18]
Bone osteosarcoma	DIST1004	Disputed	Biomarker	[19]
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[20]
Osteosarcoma	DISLQ7E2	Disputed	Biomarker	[19]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[21]
Periodontitis	DISI9JOI	Limited	Biomarker	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Suppressor of cytokine signaling 6 (SOCS6).	[23]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Suppressor of cytokine signaling 6 (SOCS6).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Suppressor of cytokine signaling 6 (SOCS6).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Suppressor of cytokine signaling 6 (SOCS6).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Suppressor of cytokine signaling 6 (SOCS6).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[24]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[30]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Suppressor of cytokine signaling 6 (SOCS6).	[31]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Suppressor of cytokine signaling 6 (SOCS6).	[32]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Suppressor of cytokine signaling 6 (SOCS6).	[31]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[33]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[34]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Suppressor of cytokine signaling 6 (SOCS6).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Suppressor of cytokine signaling 6 (SOCS6).	[40]

References

• [1] Cis-4-[18F]fluoro-D-proline detects neurodegeneration in patients with akinetic-rigid parkinsonism.Nucl Med Commun. 2019 Apr;40(4):383-387. doi: 10.1097/MNM.0000000000000982.
• [2] Expression of SHP-1 and SOCS6 in patients with acute leukemia and their clinical implication.Onco Targets Ther. 2017 Mar 29;10:1915-1920. doi: 10.2147/OTT.S131537. eCollection 2017.
• [3] Interference with NTSR1 Expression Exerts an Anti-Invasion Effect via the Jun/miR-494/SOCS6 Axis of Glioblastoma Cells.Cell Physiol Biochem. 2018;49(6):2382-2395. doi: 10.1159/000493838. Epub 2018 Sep 27.
• [4] SOCS6 Functions as a Tumor Suppressor by Inducing Apoptosis and Inhibiting Angiogenesis in Human Prostate Cancer.Curr Cancer Drug Targets. 2018;18(9):894-904. doi: 10.2174/1568009618666180102101442.
• [5] MicroRNA-let-7e regulates the progression and development of allergic rhinitis by targeting suppressor of cytokine signaling 4 and activating Janus kinase 1/signal transducer and activator of transcription 3 pathway.Exp Ther Med. 2018 Apr;15(4):3523-3529. doi: 10.3892/etm.2018.5827. Epub 2018 Feb 1.
• [6] Long noncoding RNA neuroblastoma-associated transcript 1 gene inhibits malignant cellular phenotypes of bladder cancer through miR-21/SOCS6 axis.Cell Death Dis. 2018 Oct 11;9(10):1042. doi: 10.1038/s41419-018-1090-z.
• [7] Investigation of cis-4-[(18)F]Fluoro-D-Proline Uptake in Human Brain Tumors After Multimodal Treatment.Mol Imaging Biol. 2018 Dec;20(6):1035-1043. doi: 10.1007/s11307-018-1197-8.
• [8] miR-494 inhibits cervical cancer cell proliferation through upregulation of SOCS6 expression.Oncol Lett. 2018 Mar;15(3):3075-3080. doi: 10.3892/ol.2017.7651. Epub 2017 Dec 19.
• [9] Long noncoding RNA TUSC7 inhibits cell proliferation, migration and invasion by regulating SOCS4 (SOCS5) expression through targeting miR-616 in endometrial carcinoma.Life Sci. 2019 Aug 15;231:116549. doi: 10.1016/j.lfs.2019.116549. Epub 2019 Jun 12.
• [10] miR-17-5p promotes proliferation by targeting SOCS6 in gastric cancer cells.FEBS Lett. 2014 Jun 5;588(12):2055-62. doi: 10.1016/j.febslet.2014.04.036. Epub 2014 May 5.
• [11] MiR-183 modulates multi-drug resistance in hepatocellular cancer (HCC) cells via miR-183-IDH2/SOCS6-HIF-1 feedback loop.Eur Rev Med Pharmacol Sci. 2016 May;20(10):2020-7.
• [12] Array-comparative genomic hybridization reveals loss of SOCS6 is associated with poor prognosis in primary lung squamous cell carcinoma.PLoS One. 2012;7(2):e30398. doi: 10.1371/journal.pone.0030398. Epub 2012 Feb 17.
• [13] Oxidative stress induction by cis-4-decenoic acid: relevance for MCAD deficiency.Free Radic Res. 2007 Nov;41(11):1261-72. doi: 10.1080/10715760701687109.
• [14] Downregulation of microRNA-431 by human interferon- inhibits viability of medulloblastoma and glioblastoma cells via upregulation of SOCS6.Int J Oncol. 2014 May;44(5):1685-90. doi: 10.3892/ijo.2014.2317. Epub 2014 Feb 28.
• [15] miR-1260b, mediated by YY1, activates KIT signaling by targeting SOCS6 to regulate cell proliferation and apoptosis in NSCLC.Cell Death Dis. 2019 Feb 8;10(2):112. doi: 10.1038/s41419-019-1390-y.
• [16] MicroRNA-424-5p suppresses the expression of SOCS6 in pancreatic cancer.Pathol Oncol Res. 2013 Oct;19(4):739-48. doi: 10.1007/s12253-013-9637-x. Epub 2013 May 9.
• [17] miR-494-3p overexpression promotes megakaryocytopoiesis in primary myelofibrosis hematopoietic stem/progenitor cells by targeting SOCS6.Oncotarget. 2017 Mar 28;8(13):21380-21397. doi: 10.18632/oncotarget.15226.
• [18] MiR-142-3p Suppresses SOCS6 Expression and Promotes Cell Proliferation in Nasopharyngeal Carcinoma.Cell Physiol Biochem. 2015;36(5):1743-52. doi: 10.1159/000430147.
• [19] miR-19 promotes osteosarcoma progression by targeting SOCS6.Biochem Biophys Res Commun. 2018 Jan 1;495(1):1363-1369. doi: 10.1016/j.bbrc.2017.10.002. Epub 2017 Oct 3.
• [20] kshv-mir-k12-1-5p promotes cell growth and metastasis by targeting SOCS6 in Kaposi's sarcoma cells.Cancer Manag Res. 2019 May 29;11:4985-4995. doi: 10.2147/CMAR.S198411. eCollection 2019.
• [21] miR-885-5p upregulation promotes colorectal cancer cell proliferation and migration by targeting suppressor of cytokine signaling.Oncol Lett. 2018 Jul;16(1):65-72. doi: 10.3892/ol.2018.8645. Epub 2018 May 7.
• [22] Abnormal expression of long noncoding RNA FGD5-AS1 affects the development of periodontitis through regulating miR-142-3p/SOCS6/NF-B pathway.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):2098-2106. doi: 10.1080/21691401.2019.1620256.
• [23] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [24] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [25] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [26] 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.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [29] Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation. J Biochem Mol Toxicol. 2013 Feb;27(2):106-15. doi: 10.1002/jbt.21462. Epub 2013 Jan 11.
• [30] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [31] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [32] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [35] 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.
• [36] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [37] 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.
• [38] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [39] 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.
• [40] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.