Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF25ULQ)

• DOT Name: Transcription factor SOX-10 (SOX10)
• Gene Name: SOX10
• Related Disease:
  Deaf blind hypopigmentation syndrome, Yemenite type
  Deafness
  Hirschsprung disease
  PCWH syndrome
  Schwannoma
  Triple negative breast cancer
  Uveal Melanoma
  Waardenburg syndrome type 2E
  Waardenburg syndrome type 4C
  Aplasia cutis congenita
  Astrocytoma
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma
  Charcot marie tooth disease
  Colorectal carcinoma
  Corpus callosum, agenesis of
  Hepatocellular carcinoma
  Hypopigmentation of the skin
  Malignant peripheral nerve sheath tumor
  Melanoma
  Metastatic malignant neoplasm
  Metastatic melanoma
  Multiple sclerosis
  Neoplasm
  Nerve sheath neoplasm
  Sensorineural hearing loss disorder
  Synovial sarcoma
  Trichohepatoenteric syndrome
  Vitiligo
  Waardenburg syndrome type 2A
  Cutaneous melanoma
  Prostate cancer
  Kallmann syndrome
  Waardenburg syndrome type 2
  Waardenburg-Shah syndrome
  Pelizaeus-Merzbacher-like disease
  Advanced cancer
  Demyelinating polyneuropathy
  Disorder of sexual differentiation
  Leukodystrophy
  Nervous system disease
• UniProt ID: SOX10_HUMAN
• Pfam ID: PF00505 ; PF12444
• Sequence:
  MAEEQDLSEVELSPVGSEEPRCLSPGSAPSLGPDGGGGGSGLRASPGPGELGKVKKEQQD
  GEADDDKFPVCIREAVSQVLSGYDWTLVPMPVRVNGASKSKPHVKRPMNAFMVWAQAARR
  KLADQYPHLHNAELSKTLGKLWRLLNESDKRPFIEEAERLRMQHKKDHPDYKYQPRRRKN
  GKAAQGEAECPGGEAEQGGTAAIQAHYKSAHLDHRHPGEGSPMSDGNPEHPSGQSHGPPT
  PPTTPKTELQSGKADPKRDGRSMGEGGKPHIDFGNVDIGEISHEVMSNMETFDVAELDQY
  LPPNGHPGHVSSYSAAGYGLGSALAVASGHSAWISKPPGVALPTVSPPGVDAKAQVKTET
  AGPQGPPHYTDQPSTSQIAYTSLSLPHYGSAFPSISRPQFDYSDHQPSGPYYGHSGQASG
  LYSAFSYMGPSQRPLYTAISDPSPSGPQSHSPTHWEQPVYTTLSRP
• Function: Transcription factor that plays a central role in developing and mature glia. Specifically activates expression of myelin genes, during oligodendrocyte (OL) maturation, such as DUSP15 and MYRF, thereby playing a central role in oligodendrocyte maturation and CNS myelination. Once induced, MYRF cooperates with SOX10 to implement the myelination program. Transcriptional activator of MITF, acting synergistically with PAX3. Transcriptional activator of MBP, via binding to the gene promoter.
• Tissue Specificity: Expressed in fetal brain and in adult brain, heart, small intestine and colon.
• Reactome Pathway:
  Regulation of CDH19 Expression and Function (R-HSA-9764302)
  EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Deaf blind hypopigmentation syndrome, Yemenite type	DISBQJV3	Definitive	Autosomal dominant	[1]
Deafness	DISKCLH4	Definitive	Genetic Variation	[2]
Hirschsprung disease	DISUUSM1	Definitive	Posttranslational Modification	[3]
PCWH syndrome	DISLOQND	Definitive	Autosomal dominant	[4]
Schwannoma	DISTTVLA	Definitive	Biomarker	[5]
Triple negative breast cancer	DISAMG6N	Definitive	Altered Expression	[6]
Uveal Melanoma	DISA7ZGL	Definitive	Altered Expression	[7]
Waardenburg syndrome type 2E	DISDMDVH	Definitive	Autosomal dominant	[8]
Waardenburg syndrome type 4C	DIS910BK	Definitive	Autosomal dominant	[9]
Aplasia cutis congenita	DISMDAYM	Strong	Altered Expression	[10]
Astrocytoma	DISL3V18	Strong	Biomarker	[11]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[12]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[13]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[13]
Carcinoma	DISH9F1N	Strong	Biomarker	[14]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[15]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[16]
Corpus callosum, agenesis of	DISO9P40	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[17]
Hypopigmentation of the skin	DIS39YKC	Strong	Genetic Variation	[18]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Altered Expression	[19]
Melanoma	DIS1RRCY	Strong	Biomarker	[20]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[6]
Metastatic melanoma	DISSL43L	Strong	Biomarker	[21]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[22]
Neoplasm	DISZKGEW	Strong	Biomarker	[23]
Nerve sheath neoplasm	DISJYLBY	Strong	Biomarker	[24]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[25]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[26]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[27]
Vitiligo	DISR05SL	Strong	Biomarker	[28]
Waardenburg syndrome type 2A	DISM4IVI	Strong	Genetic Variation	[29]
Cutaneous melanoma	DIS3MMH9	moderate	Biomarker	[30]
Prostate cancer	DISF190Y	moderate	Altered Expression	[31]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[8]
Waardenburg syndrome type 2	DISVZBEV	Supportive	Autosomal dominant	[32]
Waardenburg-Shah syndrome	DISR8C6R	Supportive	Autosomal dominant	[33]
Pelizaeus-Merzbacher-like disease	DISLYB1F	Disputed	Altered Expression	[34]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[35]
Demyelinating polyneuropathy	DIS7IO4W	Limited	Genetic Variation	[36]
Disorder of sexual differentiation	DISRMAEZ	Limited	Biomarker	[36]
Leukodystrophy	DISVY1TT	Limited	Genetic Variation	[37]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[38]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Transcription factor SOX-10 (SOX10) affects the response to substance of Etoposide.	[45]

2 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 Transcription factor SOX-10 (SOX10).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transcription factor SOX-10 (SOX10).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transcription factor SOX-10 (SOX10).	[40]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transcription factor SOX-10 (SOX10).	[41]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transcription factor SOX-10 (SOX10).	[41]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Transcription factor SOX-10 (SOX10).	[42]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Transcription factor SOX-10 (SOX10).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor SOX-10 (SOX10).	[44]

References

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• [3] Efficacy of Sox10 Promoter Methylation in the Diagnosis of Intestinal Neuronal Dysplasia From the Peripheral Blood.Clin Transl Gastroenterol. 2019 Dec;10(12):e00093. doi: 10.14309/ctg.0000000000000093.
• [4] Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation. Ann Neurol. 2002 Dec;52(6):836-42. doi: 10.1002/ana.10404.
• [5] Immunohistochemical Approach to the Differential Diagnosis of Meningiomas and Their Mimics.J Neuropathol Exp Neurol. 2017 Apr 1;76(4):289-298. doi: 10.1093/jnen/nlx008.
• [6] A combination of GATA3 and SOX10 is useful for the diagnosis of metastatic triple-negative breast cancer.Hum Pathol. 2019 Mar;85:221-227. doi: 10.1016/j.humpath.2018.11.005. Epub 2018 Nov 20.
• [7] SOX10 Expression as Well as BRAF and GNAQ/11 Mutations Distinguish Pigmented Ciliary Epithelium Neoplasms From Uveal Melanomas.Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5445-5451. doi: 10.1167/iovs.17-22362.
• [8] Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet. 2013 May 2;92(5):707-24. doi: 10.1016/j.ajhg.2013.03.024.
• [9] 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.
• [10] Expression Profiling of Clinical Specimens Supports the Existence of Neural Progenitor-Like Stem Cells in Basal Breast Cancers.Clin Breast Cancer. 2017 Jul;17(4):298-306.e7. doi: 10.1016/j.clbc.2017.01.007. Epub 2017 Jan 27.
• [11] SOX10 Distinguishes Pilocytic and Pilomyxoid Astrocytomas From Ependymomas but Shows No Differences in Expression Level in Ependymomas From Infants Versus Older Children or Among Molecular Subgroups.J Neuropathol Exp Neurol. 2016 Apr;75(4):295-8. doi: 10.1093/jnen/nlw010. Epub 2016 Mar 4.
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• [16] NEDD9 Inhibition by miR-25-5p Activation Is Critically Involved in Co-Treatment of Melatonin- and Pterostilbene-Induced Apoptosis in Colorectal Cancer Cells.Cancers (Basel). 2019 Oct 29;11(11):1684. doi: 10.3390/cancers11111684.
• [17] Targeting TRPV1 on cellular plasticity regulated by Ovol 2 and Zeb 1 in hepatocellular carcinoma.Biomed Pharmacother. 2019 Oct;118:109270. doi: 10.1016/j.biopha.2019.109270. Epub 2019 Aug 8.
• [18] BRG1 interacts with SOX10 to establish the melanocyte lineage and to promote differentiation.Nucleic Acids Res. 2017 Jun 20;45(11):6442-6458. doi: 10.1093/nar/gkx259.
• [19] Overexpression of PDGFRA cooperates with loss of NF1 and p53 to accelerate the molecular pathogenesis of malignant peripheral nerve sheath tumors.Oncogene. 2017 Feb 23;36(8):1058-1068. doi: 10.1038/onc.2016.269. Epub 2016 Aug 1.
• [20] Cutaneous neoplasms composed of melanoma and carcinoma: A rare but important diagnostic pitfall and review of the literature.J Cutan Pathol. 2020 Jan;47(1):36-46. doi: 10.1111/cup.13551. Epub 2019 Aug 11.
• [21] SOX10 Immunostaining in granulomatous dermatoses and benign reactive lymph nodes.J Cutan Pathol. 2019 Aug;46(8):586-590. doi: 10.1111/cup.13470. Epub 2019 May 14.
• [22] SOX10 Single Transcription Factor-Based Fast and Efficient Generation ofOligodendrocytes from Human Pluripotent Stem Cells.Stem Cell Reports. 2018 Feb 13;10(2):655-672. doi: 10.1016/j.stemcr.2017.12.014. Epub 2018 Jan 11.
• [23] Utility of Sry-Related HMG-Box Gene 10 (SOX10) as a marker of melanoma in effusion cytology.Diagn Cytopathol. 2019 Jul;47(7):653-658. doi: 10.1002/dc.24162. Epub 2019 Feb 22.
• [24] Benign epithelioid peripheral nerve sheath tumour arising in the rectum: A cytological and histological description.Diagn Cytopathol. 2019 Aug;47(8):817-820. doi: 10.1002/dc.24185. Epub 2019 Apr 8.
• [25] Key Genes and Pathways Associated With Inner Ear Malformation in SOX10?(p.R109W) Mutation Pigs.Front Mol Neurosci. 2018 Jun 5;11:181. doi: 10.3389/fnmol.2018.00181. eCollection 2018.
• [26] The Roles of Sox Family Genes in Sarcoma.Curr Drug Targets. 2016;17(15):1761-1772. doi: 10.2174/1389450117666160502145311.
• [27] Chronic constipation recognized as a sign of a SOX10 mutation in a patient with Waardenburg syndrome.Gene. 2014 May 1;540(2):258-62. doi: 10.1016/j.gene.2014.02.041. Epub 2014 Feb 28.
• [28] Identification of pathogenic genes and transcription factors in vitiligo.Dermatol Ther. 2019 Sep;32(5):e13025. doi: 10.1111/dth.13025. Epub 2019 Aug 28.
• [29] A novel dominant mutation in the SOX10 gene in a Chinese family with Waardenburg syndrome typeII.Mol Med Rep. 2019 Mar;19(3):1775-1780. doi: 10.3892/mmr.2019.9815. Epub 2019 Jan 3.
• [30] Sox10 regulates skin melanocyte proliferation by activating the DNA replication licensing factor MCM5.J Dermatol Sci. 2017 Mar;85(3):216-225. doi: 10.1016/j.jdermsci.2016.12.002. Epub 2016 Dec 5.
• [31] SOXs in human prostate cancer: implication as progression and prognosis factors.BMC Cancer. 2012 Jun 15;12:248. doi: 10.1186/1471-2407-12-248.
• [32] Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome. Hum Mutat. 2011 Dec;32(12):1436-49. doi: 10.1002/humu.21583. Epub 2011 Sep 19.
• [33] Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4. Eur J Hum Genet. 2012 Sep;20(9):990-4. doi: 10.1038/ejhg.2012.29. Epub 2012 Feb 29.
• [34] Promoter mutation is a common variant in GJC2-associated Pelizaeus-Merzbacher-like disease.Mol Genet Metab. 2011 Dec;104(4):637-43. doi: 10.1016/j.ymgme.2011.08.032. Epub 2011 Sep 8.
• [35] SOX10/keratin dual-color immunohistochemistry: An effective first-line test for the workup of epithelioid malignant neoplasms in FNA and small biopsy specimens.Cancer Cytopathol. 2018 Mar;126(3):179-189. doi: 10.1002/cncy.21960. Epub 2018 Jan 31.
• [36] 22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease.Am J Med Genet A. 2017 Apr;173(4):1066-1070. doi: 10.1002/ajmg.a.38109.
• [37] Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain.Am J Med Genet A. 2014 Feb;164A(2):542-7. doi: 10.1002/ajmg.a.36302. Epub 2013 Dec 5.
• [38] Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain.Hum Mol Genet. 2007 Dec 15;16(24):3037-46. doi: 10.1093/hmg/ddm262. Epub 2007 Sep 13.
• [39] 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.
• [40] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [41] 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.
• [42] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
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• [44] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
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