Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor SOX-8 (SOX8)
• Gene Name: SOX8
• Related Disease:
  Bilateral renal agenesis
  Campomelic dysplasia
  Cerebellar neoplasm
  Renal agenesis
  Renal hypodysplasia/aplasia 1
  Renal hypoplasia
  46,XX sex reversal 1
  Colorectal carcinoma
  Gonadal dysgenesis
  Hepatocellular carcinoma
  Lamb-Shaffer syndrome
  Multiple sclerosis
  Non-small-cell lung cancer
  Turner syndrome
  46,XY disorder of sex development
  Advanced cancer
  Waardenburg syndrome type 4A
  Breast cancer
  Breast carcinoma
  Cataract
  Microphthalmia
  Neoplasm
  Peripheral neuropathy
  Plasma cell myeloma
  Triple negative breast cancer
• UniProt ID: SOX8_HUMAN
• Pfam ID: PF00505 ; PF12444
• Sequence:
  MLDMSEARSQPPCSPSGTASSMSHVEDSDSDAPPSPAGSEGLGRAGVAVGGARGDPAEAA
  DERFPACIRDAVSQVLKGYDWSLVPMPVRGGGGGALKAKPHVKRPMNAFMVWAQAARRKL
  ADQYPHLHNAELSKTLGKLWRLLSESEKRPFVEEAERLRVQHKKDHPDYKYQPRRRKSAK
  AGHSDSDSGAELGPHPGGGAVYKAEAGLGDGHHHGDHTGQTHGPPTPPTTPKTELQQAGA
  KPELKLEGRRPVDSGRQNIDFSNVDISELSSEVMGTMDAFDVHEFDQYLPLGGPAPPEPG
  QAYGGAYFHAGASPVWAHKSAPSASASPTETGPPRPHIKTEQPSPGHYGDQPRGSPDYGS
  CSGQSSATPAAPAGPFAGSQGDYGDLQASSYYGAYPGYAPGLYQYPCFHSPRRPYASPLL
  NGLALPPAHSPTSHWDQPVYTTLTRP
• Function: Transcription factor that may play a role in central nervous system, limb and facial development. May be involved in male sex determination. Binds the consensus motif 5'-[AT][AT]CAA[AT]G-3'.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bilateral renal agenesis	DISOR5IA	Definitive	Biomarker	[1]
Campomelic dysplasia	DISVTW53	Definitive	Biomarker	[2]
Cerebellar neoplasm	DIS859E0	Definitive	Altered Expression	[3]
Renal agenesis	DIS0M9AF	Definitive	Biomarker	[1]
Renal hypodysplasia/aplasia 1	DISOH8XN	Definitive	Biomarker	[1]
Renal hypoplasia	DISJ5F10	Definitive	Biomarker	[1]
46,XX sex reversal 1	DISRDCZR	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Gonadal dysgenesis	DISIL2ZI	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Lamb-Shaffer syndrome	DIS3UI0M	Strong	Biomarker	[2]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Turner syndrome	DIS2035C	Strong	Genetic Variation	[4]
46,XY disorder of sex development	DIS78CGG	moderate	Genetic Variation	[9]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[10]
Waardenburg syndrome type 4A	DISSMGSQ	moderate	Biomarker	[11]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[10]
Cataract	DISUD7SL	Limited	Biomarker	[12]
Microphthalmia	DISGEBES	Limited	Biomarker	[12]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]
Peripheral neuropathy	DIS7KN5G	Limited	Altered Expression	[13]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[13]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	Transcription factor SOX-8 (SOX8) increases the response to substance of Bortezomib.	[13]

3 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-8 (SOX8).	[14]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the methylation of Transcription factor SOX-8 (SOX8).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor SOX-8 (SOX8).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Transcription factor SOX-8 (SOX8).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transcription factor SOX-8 (SOX8).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcription factor SOX-8 (SOX8).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transcription factor SOX-8 (SOX8).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription factor SOX-8 (SOX8).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transcription factor SOX-8 (SOX8).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcription factor SOX-8 (SOX8).	[21]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transcription factor SOX-8 (SOX8).	[22]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Transcription factor SOX-8 (SOX8).	[23]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Transcription factor SOX-8 (SOX8).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcription factor SOX-8 (SOX8).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transcription factor SOX-8 (SOX8).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Transcription factor SOX-8 (SOX8).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcription factor SOX-8 (SOX8).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor SOX-8 (SOX8).	[29]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Transcription factor SOX-8 (SOX8).	[30]

References

• [1] SOX9 controls epithelial branching by activating RET effector genes during kidney development.Hum Mol Genet. 2011 Mar 15;20(6):1143-53. doi: 10.1093/hmg/ddq558. Epub 2011 Jan 6.
• [2] Roles and regulation of SOX transcription factors in skeletogenesis.Curr Top Dev Biol. 2019;133:171-193. doi: 10.1016/bs.ctdb.2019.01.007. Epub 2019 Feb 26.
• [3] Sox8 gene expression identifies immature glial cells in developing cerebellum and cerebellar tumours.Brain Res Mol Brain Res. 2001 Aug 15;92(1-2):193-200. doi: 10.1016/s0169-328x(01)00147-4.
• [4] Genetic evaluation of disorders of sex development: current practice and novel gene discovery.Curr Opin Endocrinol Diabetes Obes. 2019 Feb;26(1):54-59. doi: 10.1097/MED.0000000000000452.
• [5] Over-expression of SOX8 predicts poor prognosis in colorectal cancer: A retrospective study.Medicine (Baltimore). 2019 Jul;98(27):e16237. doi: 10.1097/MD.0000000000016237.
• [6] Oncogenicity of the transcription factor SOX8 in hepatocellular carcinoma.Med Oncol. 2014 Apr;31(4):918. doi: 10.1007/s12032-014-0918-3. Epub 2014 Mar 19.
• [7] MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.Brain. 2013 Jun;136(Pt 6):1778-82. doi: 10.1093/brain/awt101.
• [8] miRNA-124 down-regulates SOX8 expression and suppresses cell proliferation in non-small cell lung cancer.Int J Clin Exp Pathol. 2014 Sep 15;7(10):6534-42. eCollection 2014.
• [9] Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.Hum Mol Genet. 2018 Apr 1;27(7):1228-1240. doi: 10.1093/hmg/ddy037.
• [10] SOX8 acts as a prognostic factor and mediator to regulate the progression of triple-negative breast cancer.Carcinogenesis. 2019 Oct 16;40(10):1278-1287. doi: 10.1093/carcin/bgz034.
• [11] The SOXE transcription factors-SOX8, SOX9and SOX10-share a bi-partite transactivation mechanism.Nucleic Acids Res. 2019 Jul 26;47(13):6917-6931. doi: 10.1093/nar/gkz523.
• [12] Cloning and characterisation of the Sry-related transcription factor gene Sox8.Nucleic Acids Res. 2000 Mar 15;28(6):1473-80. doi: 10.1093/nar/28.6.1473.
• [13] Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. doi: 10.1016/S1470-2045(10)70206-0. Epub 2010 Sep 21.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [20] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] 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.
• [23] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [24] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes. Environ Toxicol. 2019 Apr;34(4):401-414.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [31] Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. doi: 10.1016/S1470-2045(10)70206-0. Epub 2010 Sep 21.