Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM8OZWV)

• DOT Name: Paired amphipathic helix protein Sin3a (SIN3A)
• Synonyms: Histone deacetylase complex subunit Sin3a; Transcriptional corepressor Sin3a
• Gene Name: SIN3A
• Related Disease:
  Acute myelogenous leukaemia
  SIN3A-related intellectual disability syndrome
  Advanced cancer
  Autism spectrum disorder
  Autism, susceptibility to, 15
  Chromosome 15q24 deletion syndrome
  Communicating hydrocephalus
  Congenital hydrocephalus
  Corpus callosum, agenesis of
  Fatty liver disease
  Hydrocephalus
  Isolated congenital microcephaly
  Lung neoplasm
  Microlissencephaly
  Multiple endocrine neoplasia type 2
  Multiple endocrine neoplasia type 2A
  Myelodysplastic syndrome
  Neoplasm
  Non-small-cell lung cancer
  Retinoblastoma
  Triple negative breast cancer
  Breast cancer
  Breast carcinoma
  Intellectual disability
  SIN3A-related intellectual disability syndrome due to a point mutation
  Congenital diaphragmatic hernia
  Cutaneous squamous cell carcinoma
  Fetal growth restriction
  Hepatocellular carcinoma
  Neuroblastoma
• UniProt ID: SIN3A_HUMAN
• Pfam ID: PF02671 ; PF08295 ; PF16879
• Sequence:
  MKRRLDDQESPVYAAQQRRIPGSTEAFPHQHRVLAPAPPVYEAVSETMQSATGIQYSVTP
  SYQVSAMPQSSGSHGPAIAAVHSSHHHPTAVQPHGGQVVQSHAHPAPPVAPVQGQQQFQR
  LKVEDALSYLDQVKLQFGSQPQVYNDFLDIMKEFKSQSIDTPGVISRVSQLFKGHPDLIM
  GFNTFLPPGYKIEVQTNDMVNVTTPGQVHQIPTHGIQPQPQPPPQHPSQPSAQSAPAPAQ
  PAPQPPPAKVSKPSQLQAHTPASQQTPPLPPYASPRSPPVQPHTPVTISLGTAPSLQNNQ
  PVEFNHAINYVNKIKNRFQGQPDIYKAFLEILHTYQKEQRNAKEAGGNYTPALTEQEVYA
  QVARLFKNQEDLLSEFGQFLPDANSSVLLSKTTAEKVDSVRNDHGGTVKKPQLNNKPQRP
  SQNGCQIRRHPTGTTPPVKKKPKLLNLKDSSMADASKHGGGTESLFFDKVRKALRSAEAY
  ENFLRCLVIFNQEVISRAELVQLVSPFLGKFPELFNWFKNFLGYKESVHLETYPKERATE
  GIAMEIDYASCKRLGSSYRALPKSYQQPKCTGRTPLCKEVLNDTWVSFPSWSEDSTFVSS
  KKTQYEEHIYRCEDERFELDVVLETNLATIRVLEAIQKKLSRLSAEEQAKFRLDNTLGGT
  SEVIHRKALQRIYADKAADIIDGLRKNPSIAVPIVLKRLKMKEEEWREAQRGFNKVWREQ
  NEKYYLKSLDHQGINFKQNDTKVLRSKSLLNEIESIYDERQEQATEENAGVPVGPHLSLA
  YEDKQILEDAAALIIHHVKRQTGIQKEDKYKIKQIMHHFIPDLLFAQRGDLSDVEEEEEE
  EMDVDEATGAVKKHNGVGGSPPKSKLLFSNTAAQKLRGMDEVYNLFYVNNNWYIFMRLHQ
  ILCLRLLRICSQAERQIEEENREREWEREVLGIKRDKSDSPAIQLRLKEPMDVDVEDYYP
  AFLDMVRSLLDGNIDSSQYEDSLREMFTIHAYIAFTMDKLIQSIVRQLQHIVSDEICVQV
  TDLYLAENNNGATGGQLNTQNSRSLLESTYQRKAEQLMSDENCFKLMFIQSQGQVQLTIE
  LLDTEEENSDDPVEAERWSDYVERYMNSDTTSPELREHLAQKPVFLPRNLRRIRKCQRGR
  EQQEKEGKEGNSKKTMENVDSLDKLECRFKLNSYKMVYVIKSEDYMYRRTALLRAHQSHE
  RVSKRLHQRFQAWVDKWTKEHVPREMAAETSKWLMGEGLEGLVPCTTTCDTETLHFVSIN
  KYRVKYGTVFKAP
• Function: Acts as a transcriptional repressor. Corepressor for REST. Interacts with MXI1 to repress MYC responsive genes and antagonize MYC oncogenic activities. Also interacts with MXD1-MAX heterodimers to repress transcription by tethering SIN3A to DNA. Acts cooperatively with OGT to repress transcription in parallel with histone deacetylation. Involved in the control of the circadian rhythms. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex through histone deacetylation. Cooperates with FOXK1 to regulate cell cycle progression probably by repressing cell cycle inhibitor genes expression. Required for cortical neuron differentiation and callosal axon elongation.
• Tissue Specificity: Expressed in the developing brain, with highest levels of expression detected in the ventricular zone of various cortical regions.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Thyroid hormone sig.ling pathway (hsa04919)
  Huntington disease (hsa05016)
  Epstein-Barr virus infection (hsa05169)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Regulation of lipid metabolism by PPARalpha (R-HSA-400206)
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Loss of MECP2 binding ability to 5mC-DNA (R-HSA-9022538)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  MECP2 regulates neuronal receptors and channels (R-HSA-9022699)
  MECP2 regulates transcription of neuronal ligands (R-HSA-9022702)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  STAT3 nuclear events downstream of ALK signaling (R-HSA-9701898)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  SUMOylation of transcription cofactors (R-HSA-3899300)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
SIN3A-related intellectual disability syndrome	DISCAQTR	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[4]
Autism, susceptibility to, 15	DISYCG6A	Strong	Autosomal dominant	[4]
Chromosome 15q24 deletion syndrome	DISQ7BDK	Strong	Autosomal dominant	[5]
Communicating hydrocephalus	DIS33112	Strong	Biomarker	[4]
Congenital hydrocephalus	DIS7O6UL	Strong	Biomarker	[4]
Corpus callosum, agenesis of	DISO9P40	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[6]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[4]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[4]
Lung neoplasm	DISVARNB	Strong	Posttranslational Modification	[7]
Microlissencephaly	DISUCKNT	Strong	Biomarker	[4]
Multiple endocrine neoplasia type 2	DISPQ4Y5	Strong	Biomarker	[8]
Multiple endocrine neoplasia type 2A	DIS7D3W2	Strong	Biomarker	[8]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[11]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[12]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[13]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[14]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[14]
Intellectual disability	DISMBNXP	moderate	Biomarker	[4]
SIN3A-related intellectual disability syndrome due to a point mutation	DISGR8IJ	Supportive	Autosomal dominant	[4]
Congenital diaphragmatic hernia	DIS0IPVU	Limited	Autosomal dominant	[5]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[15]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[17]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Paired amphipathic helix protein Sin3a (SIN3A).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Paired amphipathic helix protein Sin3a (SIN3A).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Paired amphipathic helix protein Sin3a (SIN3A).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Paired amphipathic helix protein Sin3a (SIN3A).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Paired amphipathic helix protein Sin3a (SIN3A).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Paired amphipathic helix protein Sin3a (SIN3A).	[25]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Paired amphipathic helix protein Sin3a (SIN3A).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Paired amphipathic helix protein Sin3a (SIN3A).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the methylation of Paired amphipathic helix protein Sin3a (SIN3A).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Paired amphipathic helix protein Sin3a (SIN3A).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Paired amphipathic helix protein Sin3a (SIN3A).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Paired amphipathic helix protein Sin3a (SIN3A).	[27]

References

• [1] Identification of Novel Functional Variants of SIN3A and SRSF1 among Somatic Variants in Acute Myeloid Leukemia Patients.Mol Cells. 2018 May 31;41(5):465-475. doi: 10.14348/molcells.2018.0051. Epub 2018 May 15.
• [2] 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.
• [3] Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells.Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11811-6. doi: 10.1073/pnas.1006737107. Epub 2010 Jun 14.
• [4] Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity. Nat Genet. 2016 Aug;48(8):877-87. doi: 10.1038/ng.3619. Epub 2016 Jul 11.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling.Cell. 2017 Nov 2;171(4):824-835.e18. doi: 10.1016/j.cell.2017.09.045. Epub 2017 Oct 19.
• [7] Decreased expression of the SIN3A gene, a candidate tumor suppressor located at the prevalent allelic loss region 15q23 in non-small cell lung cancer.Lung Cancer. 2008 Jan;59(1):24-31. doi: 10.1016/j.lungcan.2007.08.002. Epub 2007 Sep 12.
• [8] Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors.Oncogene. 2013 Jun 27;32(26):3184-97. doi: 10.1038/onc.2012.326. Epub 2012 Aug 13.
• [9] t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders.Mol Cancer. 2015 Dec 16;14:211. doi: 10.1186/s12943-015-0484-0.
• [10] The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3.Cancer Res. 2019 Jun 15;79(12):3076-3087. doi: 10.1158/0008-5472.CAN-18-0359. Epub 2019 Jan 28.
• [11] miR-210-3p regulates the proliferation and apoptosis of non-small cell lung cancer cells by targeting SIN3A.Exp Ther Med. 2019 Oct;18(4):2565-2573. doi: 10.3892/etm.2019.7867. Epub 2019 Aug 8.
• [12] How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation.PLoS Comput Biol. 2013;9(8):e1003210. doi: 10.1371/journal.pcbi.1003210. Epub 2013 Aug 29.
• [13] Probing the interaction between the histone methyltransferase/deacetylase subunit RBBP4/7 and the transcription factor BCL11A in epigenetic complexes.J Biol Chem. 2018 Feb 9;293(6):2125-2136. doi: 10.1074/jbc.M117.811463. Epub 2017 Dec 20.
• [14] A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ER expression.Sci Rep. 2018 Oct 30;8(1):16000. doi: 10.1038/s41598-018-34290-1.
• [15] Nuclear FAK and Runx1 Cooperate to Regulate IGFBP3, Cell-Cycle Progression, and Tumor Growth.Cancer Res. 2017 Oct 1;77(19):5301-5312. doi: 10.1158/0008-5472.CAN-17-0418. Epub 2017 Aug 14.
• [16] Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1.J Clin Invest. 2008 Jun;118(6):2316-24. doi: 10.1172/JCI33655.
• [17] Key signaling pathways, genes and transcription factors associated with hepatocellular carcinoma.Mol Med Rep. 2018 Jun;17(6):8153-8160. doi: 10.3892/mmr.2018.8871. Epub 2018 Apr 12.
• [18] ARID1A-SIN3A drives retinoic acid-induced neuroblastoma differentiation by transcriptional repression of TERT.Mol Carcinog. 2019 Nov;58(11):1998-2007. doi: 10.1002/mc.23091. Epub 2019 Jul 31.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] 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.
• [21] 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.
• [22] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [23] 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.
• [24] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.