Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0QWHK4)

• DOT Name: Single-minded homolog 2 (SIM2)
• Synonyms: Class E basic helix-loop-helix protein 15; bHLHe15
• Gene Name: SIM2
• Related Disease:
  Benign prostatic hyperplasia
  Intellectual disability
  Alzheimer disease
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoid tumor
  Carcinoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Ductal breast carcinoma in situ
  Glioblastoma multiforme
  Glioma
  Intervertebral disc degeneration
  Isolated cleft palate
  Mental disorder
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Pheochromocytoma
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Colorectal carcinoma
  Hepatocellular carcinoma
  Hirschsprung disease
  Leukemia
  Pancreatic cancer
  Holoprosencephaly
  Invasive breast carcinoma
  Breast neoplasm
  Invasive ductal breast carcinoma
  Malignant pleural mesothelioma
• UniProt ID: SIM2_HUMAN
• Pfam ID: PF00010 ; PF00989 ; PF08447 ; PF06621
• Sequence:
  MKEKSKNAAKTRREKENGEFYELAKLLPLPSAITSQLDKASIIRLTTSYLKMRAVFPEGL
  GDAWGQPSRAGPLDGVAKELGSHLLQTLDGFVFVVASDGKIMYISETASVHLGLSQVELT
  GNSIYEYIHPSDHDEMTAVLTAHQPLHHHLLQEYEIERSFFLRMKCVLAKRNAGLTCSGY
  KVIHCSGYLKIRQYMLDMSLYDSCYQIVGLVAVGQSLPPSAITEIKLYSNMFMFRASLDL
  KLIFLDSRVTEVTGYEPQDLIEKTLYHHVHGCDVFHLRYAHHLLLVKGQVTTKYYRLLSK
  RGGWVWVQSYATVVHNSRSSRPHCIVSVNYVLTEIEYKELQLSLEQVSTAKSQDSWRTAL
  STSQETRKLVKPKNTKMKTKLRTNPYPPQQYSSFQMDKLECGQLGNWRASPPASAAAPPE
  LQPHSESSDLLYTPSYSLPFSYHYGHFPLDSHVFSSKKPMLPAKFGQPQGSPCEVARFFL
  STLPASGECQWHYANPLVPSSSSPAKNPPEPPANTARHSLVPSYEAPAAAVRRFGEDTAP
  PSFPSCGHYREEPALGPAKAARQAARDGARLALARAAPECCAPPTPEAPGAPAQLPFVLL
  NYHRVLARRGPLGGAAPAASGLACAPGGPEAATGALRLRHPSPAATSPPGAPLPHYLGAS
  VIITNGR
• Function: Transcription factor that may be a master gene of CNS development in cooperation with Arnt. It may have pleiotropic effects in the tissues expressed during development.

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Benign prostatic hyperplasia	DISI3CW2	Definitive	Altered Expression	[1]
Intellectual disability	DISMBNXP	Definitive	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Carcinoid tumor	DISMNRDC	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[8]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[11]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[12]
Mental disorder	DIS3J5R8	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[15]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[7]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[17]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[17]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[18]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[19]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[20]
Hirschsprung disease	DISUUSM1	moderate	Altered Expression	[21]
Leukemia	DISNAKFL	moderate	Biomarker	[22]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[23]
Holoprosencephaly	DISR35EC	Disputed	Biomarker	[24]
Invasive breast carcinoma	DISANYTW	Disputed	Biomarker	[25]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[25]
Invasive ductal breast carcinoma	DIS43J58	Limited	Biomarker	[9]
Malignant pleural mesothelioma	DIST2R60	Limited	Biomarker	[26]

6 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 Single-minded homolog 2 (SIM2).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Single-minded homolog 2 (SIM2).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Single-minded homolog 2 (SIM2).	[29]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Single-minded homolog 2 (SIM2).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Single-minded homolog 2 (SIM2).	[33]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Single-minded homolog 2 (SIM2).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Single-minded homolog 2 (SIM2).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Single-minded homolog 2 (SIM2).	[32]

References

• [1] Down's syndrome-associated single minded gene as a novel tumor marker.Anticancer Res. 2002 Nov-Dec;22(6A):3149-57.
• [2] Spatial and temporal localization during embryonic and fetal human development of the transcription factor SIM2 in brain regions altered in Down syndrome.Int J Dev Neurosci. 2005 Aug;23(5):475-84. doi: 10.1016/j.ijdevneu.2005.05.004.
• [3] Ethanol Activation of PKA Mediates Single-Minded 2 Expression in Neuronal Cells.Mol Neurobiol. 2015 Dec;52(3):1234-1244. doi: 10.1007/s12035-014-8924-1. Epub 2014 Oct 17.
• [4] Single minded 2-s (SIM2-s) gene is expressed in human GBM cells and involved in GBM invasion.Cancer Biol Ther. 2010 Mar 15;9(6):430-6. doi: 10.4161/cbt.9.6.10892. Epub 2010 Mar 8.
• [5] Loss of SIM2s inhibits RAD51 binding and leads to unresolved replication stress.Breast Cancer Res. 2019 Nov 27;21(1):125. doi: 10.1186/s13058-019-1207-z.
• [6] Analysis of multiple molecular changes in human endocrine tumours.Surg Oncol. 1994 Jun;3(3):153-9. doi: 10.1016/0960-7404(94)90044-2.
• [7] Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors.Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4760-5. doi: 10.1073/pnas.0831000100. Epub 2003 Apr 3.
• [8] Inhibition of Single Minded 2 gene expression mediates tumor-selective apoptosis and differentiation in human colon cancer cells.Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12765-70. doi: 10.1073/pnas.0505484102. Epub 2005 Aug 29.
• [9] ATM-dependent activation of SIM2s regulates homologous recombination and epithelial-mesenchymal transition.Oncogene. 2019 Apr;38(14):2611-2626. doi: 10.1038/s41388-018-0622-4. Epub 2018 Dec 10.
• [10] Targeting SIM2-s decreases glioma cell invasion through mesenchymal--epithelial transition.J Cell Biochem. 2014 Nov;115(11):1900-7. doi: 10.1002/jcb.24859.
• [11] Orally administered simvastatin partially preserves lumbar vertebral bone mass but not integrity of intervertebral discs in ovariectomized rats.Exp Ther Med. 2017 Mar;13(3):877-884. doi: 10.3892/etm.2017.4043. Epub 2017 Jan 13.
• [12] Craniofacial abnormalities resulting from targeted disruption of the murine Sim2 gene.Dev Dyn. 2002 Aug;224(4):373-80. doi: 10.1002/dvdy.10116.
• [13] Developing and testing the F-SIM, a measure of social inclusion for people with mental illness.Psychiatry Res. 2019 Sep;279:1-8. doi: 10.1016/j.psychres.2019.06.038. Epub 2019 Jun 26.
• [14] Cross-talk between SIM2s and NFB regulates cyclooxygenase 2 expression in breast cancer.Breast Cancer Res. 2019 Nov 29;21(1):131. doi: 10.1186/s13058-019-1224-y.
• [15] Potential Antitumor Activity of SIM-89 in Non-Small Cell Lung Cancer Cells.Yonsei Med J. 2017 May;58(3):581-591. doi: 10.3349/ymj.2017.58.3.581.
• [16] Quantitative superresolution microscopy reveals differences in nuclear DNA organization of multiple myeloma and monoclonal gammopathy of undetermined significance.J Cell Biochem. 2015 May;116(5):704-10. doi: 10.1002/jcb.25030.
• [17] Circulating mRNAs and miRNAs as candidate markers for the diagnosis and prognosis of prostate cancer.PLoS One. 2017 Sep 14;12(9):e0184094. doi: 10.1371/journal.pone.0184094. eCollection 2017.
• [18] The role of the transcription factor SIM2 in prostate cancer.PLoS One. 2011;6(12):e28837. doi: 10.1371/journal.pone.0028837. Epub 2011 Dec 9.
• [19] Long noncoding RNA TMEM75 promotes colorectal cancer progression by activation of SIM2.Gene. 2018 Oct 30;675:80-87. doi: 10.1016/j.gene.2018.06.096. Epub 2018 Jun 30.
• [20] Super-SILAC mix coupled with SIM/AIMS assays for targeted verification of phosphopeptides discovered in a large-scale phosphoproteome analysis of hepatocellular carcinoma.J Proteomics. 2017 Mar 22;157:40-51. doi: 10.1016/j.jprot.2017.02.005. Epub 2017 Feb 10.
• [21] Variants in RET associated with Hirschsprung's disease affect binding of transcription factors and gene expression.Gastroenterology. 2011 Feb;140(2):572-582.e2. doi: 10.1053/j.gastro.2010.10.044. Epub 2010 Oct 25.
• [22] Embryonic stem cell derived germ cells induce spermatogenesis after transplantation into the testes of an adult mouse azoospermia model.Clin Sci (Lond). 2017 Sep 8;131(18):2381-2395. doi: 10.1042/CS20171074. Print 2017 Sep 15.
• [23] The HIF1alpha-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element.Oncogene. 2009 Oct 15;28(41):3671-80. doi: 10.1038/onc.2009.228. Epub 2009 Aug 10.
• [24] Physical mapping of the holoprosencephaly critical region in 21q22.3, exclusion of SIM2 as a candidate gene for holoprosencephaly, and mapping of SIM2 to a region of chromosome 21 important for Down syndrome.Am J Hum Genet. 1995 Nov;57(5):1074-9.
• [25] Regulation of DCIS to invasive breast cancer progression by Singleminded-2s (SIM2s).Oncogene. 2013 May 23;32(21):2631-9. doi: 10.1038/onc.2012.286. Epub 2012 Jul 9.
• [26] Data-driven information retrieval in heterogeneous collections of transcriptomics data links SIM2s to malignant pleural mesothelioma.Bioinformatics. 2012 Jan 15;28(2):246-53. doi: 10.1093/bioinformatics/btr634. Epub 2011 Nov 20.
• [27] 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.
• [28] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [29] 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.
• [30] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [31] 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.
• [32] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [33] 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.
• [34] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.