Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFB59FK)

• DOT Name: Paired amphipathic helix protein Sin3b (SIN3B)
• Synonyms: Histone deacetylase complex subunit Sin3b; Transcriptional corepressor Sin3b
• Gene Name: SIN3B
• Related Disease:
  Advanced cancer
  Breast neoplasm
  Hepatocellular carcinoma
  Matthew-Wood syndrome
  Neoplasm
  Pancreatic cancer
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Triple negative breast cancer
  Breast cancer
  Breast carcinoma
  SIN3A-related intellectual disability syndrome due to a point mutation
• UniProt ID: SIN3B_HUMAN
• PDB ID: 8BPA; 8BPB; 8BPC; 8C60
• Pfam ID: PF02671 ; PF08295 ; PF16879
• Sequence:
  MAHAGGGSGGSGAGGPAGRGLSGARWGRSGSAGHEKLPVHVEDALTYLDQVKIRFGSDPA
  TYNGFLEIMKEFKSQSIDTPGVIRRVSQLFHEHPDLIVGFNAFLPLGYRIDIPKNGKLNI
  QSPLTSQENSHNHGDGAEDFKQQVPYKEDKPQVPLESDSVEFNNAISYVNKIKTRFLDHP
  EIYRSFLEILHTYQKEQLNTRGRPFRGMSEEEVFTEVANLFRGQEDLLSEFGQFLPEAKR
  SLFTGNGPCEMHSVQKNEHDKTPEHSRKRSRPSLLRPVSAPAKKKMKLRGTKDLSIAAVG
  KYGTLQEFSFFDKVRRVLKSQEVYENFLRCIALFNQELVSGSELLQLVSPFLGKFPELFA
  QFKSFLGVKELSFAPPMSDRSGDGISREIDYASCKRIGSSYRALPKTYQQPKCSGRTAIC
  KELDHWTLLQGSWTDDYCMSKFKNTCWIPGYSAGVLNDTWVSFPSWSEDSTFVSSKKTPY
  EEQLHRCEDERFELDVVLETNLATIRVLESVQKKLSRMAPEDQEKFRLDDSLGGTSEVIQ
  RRAIYRIYGDKAPEIIESLKKNPVTAVPVVLKRLKAKEEEWREAQQGFNKIWREQYEKAY
  LKSLDHQAVNFKQNDTKALRSKSLLNEIESVYDEHQEQHSEGRSAPSSEPHLIFVYEDRQ
  ILEDAAALISYYVKRQPAIQKEDQGTIHQLLHQFVPSLFFSQQLDLGASEESADEDRDSP
  QGQTTDPSERKKPAPGPHSSPPEEKGAFGDAPATEQPPLPPPAPHKPLDDVYSLFFANNN
  WYFFLRLHQTLCSRLLKIYRQAQKQLLEYRTEKEREKLLCEGRREKGSDPAMELRLKQPS
  EVELEEYYPAFLDMVRSLLEGSIDPTQYEDTLREMFTIHAYVGFTMDKLVQNIARQLHHL
  VSDDVCLKVVELYLNEKKRGAAGGNLSSRCVRAARETSYQWKAERCMADENCFKVMFLQR
  KGQVIMTIELLDTEEAQTEDPVEVQHLARYVEQYVGTEGASSSPTEGFLLKPVFLQRNLK
  KFRRRWQSEQARALRGEARSSWKRLVGVESACDVDCRFKLSTHKMVFIVNSEDYMYRRGT
  LCRAKQVQPLVLLRHHQHFEEWHSRWLEDNVTVEAASLVQDWLMGEEDEDMVPCKTLCET
  VHVHGLPVTRYRVQYSRRPASP
• Function: Acts as a transcriptional repressor. Interacts with MXI1 to repress MYC responsive genes and antagonize MYC oncogenic activities. Interacts with MAD-MAX heterodimers by binding to MAD. The heterodimer then represses transcription by tethering SIN3B to DNA. Also forms a complex with FOXK1 which represses transcription. With FOXK1, regulates cell cycle progression probably by repressing cell cycle inhibitor genes expression. As part of the SIN3B complex represses transcription and counteracts the histone acetyltransferase activity of EP300 through the recognition H3K27ac marks by PHF12 and the activity of the histone deacetylase HDAC2. SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription.
• Reactome Pathway:
  (Name not found)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  NoRC negatively regulates rRNA expression (R-HSA-427413)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Pancreatic cancer	DISJC981	Strong	Biomarker	[4]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[7]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[7]
SIN3A-related intellectual disability syndrome due to a point mutation	DISGR8IJ	Supportive	Autosomal dominant	[8]

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 Paired amphipathic helix protein Sin3b (SIN3B).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Paired amphipathic helix protein Sin3b (SIN3B).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Paired amphipathic helix protein Sin3b (SIN3B).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Paired amphipathic helix protein Sin3b (SIN3B).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Paired amphipathic helix protein Sin3b (SIN3B).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Paired amphipathic helix protein Sin3b (SIN3B).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Paired amphipathic helix protein Sin3b (SIN3B).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Paired amphipathic helix protein Sin3b (SIN3B).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Paired amphipathic helix protein Sin3b (SIN3B).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Paired amphipathic helix protein Sin3b (SIN3B).	[17]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Paired amphipathic helix protein Sin3b (SIN3B).	[19]

References

• [1] The potential of targeting Sin3B and its associated complexes for cancer therapy.Expert Opin Ther Targets. 2017 Nov;21(11):1051-1061. doi: 10.1080/14728222.2017.1386655. Epub 2017 Oct 9.
• [2] Sin3b interacts with Myc and decreases Myc levels.J Biol Chem. 2014 Aug 8;289(32):22221-36. doi: 10.1074/jbc.M113.538744. Epub 2014 Jun 20.
• [3] SIN3B promotes integrin V subunit gene transcription and cell migration of hepatocellular carcinoma.J Mol Cell Biol. 2019 May 1;11(5):421-432. doi: 10.1093/jmcb/mjy050.
• [4] Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression.J Clin Invest. 2014 May;124(5):2125-35. doi: 10.1172/JCI72619. Epub 2014 Apr 1.
• [5] Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence.Cancer Res. 2017 Oct 1;77(19):5339-5348. doi: 10.1158/0008-5472.CAN-16-3410. Epub 2017 Aug 14.
• [6] SIN3A and SIN3B differentially regulate breast cancer metastasis.Oncotarget. 2016 Nov 29;7(48):78713-78725. doi: 10.18632/oncotarget.12805.
• [7] Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131.J Biol Chem. 2016 Apr 1;291(14):7313-24. doi: 10.1074/jbc.M115.701227. Epub 2016 Feb 3.
• [8] Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder. Am J Hum Genet. 2021 May 6;108(5):929-941. doi: 10.1016/j.ajhg.2021.03.017. Epub 2021 Apr 2.
• [9] 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.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] 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.
• [19] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.