Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2IQJUC)

• DOT Name: SUN domain-containing protein 2 (SUN2)
• Synonyms: Protein unc-84 homolog B; Rab5-interacting protein; Rab5IP; Sad1/unc-84 protein-like 2
• Gene Name: SUN2
• Related Disease:
  Prostate carcinoma
  Amyotrophic lateral sclerosis
  Atypical teratoid/rhabdoid tumour
  Breast cancer
  Breast carcinoma
  Cerebellar ataxia
  Charlevoix-Saguenay spastic ataxia
  Duchenne muscular dystrophy
  Embryonal neoplasm
  Emery-Dreifuss muscular dystrophy
  HIV infectious disease
  Lung cancer
  Lung carcinoma
  Mandibuloacral dysplasia
  Medulloblastoma
  Myopathy
  Neoplasm
  Prostate cancer
  Tetralogy of fallot
  Advanced cancer
• UniProt ID: SUN2_HUMAN
• PDB ID: 3UNP; 4DXR; 4DXS; 4DXT; 4FI9; 6WMD; 6WME; 6WMF; 6WMG
• Pfam ID: PF18580 ; PF07738
• Sequence:
  MSRRSQRLTRYSQGDDDGSSSSGGSSVAGSQSTLFKDSPLRTLKRKSSNMKRLSPAPQLG
  PSSDAHTSYYSESLVHESWFPPRSSLEELHGDANWGEDLRVRRRRGTGGSESSRASGLVG
  RKATEDFLGSSSGYSSEDDYVGYSDVDQQSSSSRLRSAVSRAGSLLWMVATSPGRLFRLL
  YWWAGTTWYRLTTAASLLDVFVLTRRFSSLKTFLWFLLPLLLLTCLTYGAWYFYPYGLQT
  FHPALVSWWAAKDSRRPDEGWEARDSSPHFQAEQRVMSRVHSLERRLEALAAEFSSNWQK
  EAMRLERLELRQGAPGQGGGGGLSHEDTLALLEGLVSRREAALKEDFRRETAARIQEELS
  ALRAEHQQDSEDLFKKIVRASQESEARIQQLKSEWQSMTQESFQESSVKELRRLEDQLAG
  LQQELAALALKQSSVAEEVGLLPQQIQAVRDDVESQFPAWISQFLARGGGGRVGLLQREE
  MQAQLRELESKILTHVAEMQGKSAREAAASLSLTLQKEGVIGVTEEQVHHIVKQALQRYS
  EDRIGLADYALESGGASVISTRCSETYETKTALLSLFGIPLWYHSQSPRVILQPDVHPGN
  CWAFQGPQGFAVVRLSARIRPTAVTLEHVPKALSPNSTISSAPKDFAIFGFDEDLQQEGT
  LLGKFTYDQDGEPIQTFHFQAPTMATYQVVELRILTNWGHPEYTCIYRFRVHGEPAH
• Function: As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex, involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. Specifically, SYNE2 and SUN2 assemble in arrays of transmembrane actin-associated nuclear (TAN) lines which are bound to F-actin cables and couple the nucleus to retrograde actin flow during actin-dependent nuclear movement. Required for interkinetic nuclear migration (INM) and essential for nucleokinesis and centrosome-nucleus coupling during radial neuronal migration in the cerebral cortex and during glial migration. Required for nuclear migration in retinal photoreceptor progenitors implicating association with cytoplasmic dynein-dynactin and kinesin motor complexes, and probably B-type lamins; SUN1 and SUN2 seem to act redundantly. The SUN1/2:KASH5 LINC complex couples telomeres to microtubules during meiosis; SUN1 and SUN2 seem to act at least partial redundantly. Anchors chromosome movement in the prophase of meiosis and is involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis. Required for telomere attachment to nuclear envelope and gametogenesis. May also function on endocytic vesicles as a receptor for RAB5-GDP and participate in the activation of RAB5.
• Tissue Specificity: Widely expressed. Highly expressed in heart, lung and muscle. Weakly expressed in fetal heart. Slightly overexpressed in some heart tissues form patients with congenital heart defects.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Meiotic synapsis (R-HSA-1221632)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate carcinoma	DISMJPLE	Definitive	Genetic Variation	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[2]
Atypical teratoid/rhabdoid tumour	DIS1FA0D	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[5]
Charlevoix-Saguenay spastic ataxia	DISE8X81	Strong	Biomarker	[5]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[6]
Embryonal neoplasm	DIS5MQSB	Strong	Altered Expression	[3]
Emery-Dreifuss muscular dystrophy	DISYTPR5	Strong	Genetic Variation	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Mandibuloacral dysplasia	DISMOYL1	Strong	Biomarker	[9]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[3]
Myopathy	DISOWG27	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[1]
Tetralogy of fallot	DISMHFNW	Strong	Biomarker	[12]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]

4 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 SUN domain-containing protein 2 (SUN2).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of SUN domain-containing protein 2 (SUN2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of SUN domain-containing protein 2 (SUN2).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of SUN domain-containing protein 2 (SUN2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SUN domain-containing protein 2 (SUN2).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of SUN domain-containing protein 2 (SUN2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SUN domain-containing protein 2 (SUN2).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of SUN domain-containing protein 2 (SUN2).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of SUN domain-containing protein 2 (SUN2).	[18]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of SUN domain-containing protein 2 (SUN2).	[19]
Aspirin	DM672AH	Approved	Aspirin increases the expression of SUN domain-containing protein 2 (SUN2).	[20]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of SUN domain-containing protein 2 (SUN2).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of SUN domain-containing protein 2 (SUN2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SUN domain-containing protein 2 (SUN2).	[22]

References

• [1] 12 new susceptibility loci for prostate cancer identified by genome-wide association study in Japanese population.Nat Commun. 2019 Sep 27;10(1):4422. doi: 10.1038/s41467-019-12267-6.
• [2] Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat.Neurobiol Aging. 2013 Sep;34(9):2234.e1-7. doi: 10.1016/j.neurobiolaging.2013.03.003. Epub 2013 Apr 12.
• [3] Downregulation of SUN2, a novel tumor suppressor, mediates miR-221/222-induced malignancy in central nervous system embryonal tumors.Carcinogenesis. 2014 Oct;35(10):2164-74. doi: 10.1093/carcin/bgu105. Epub 2014 May 15.
• [4] Differential expression and molecular interactions of chromosome region maintenance 1 and calreticulin exportins in breast cancer cells.J Steroid Biochem Mol Biol. 2019 Jan;185:7-16. doi: 10.1016/j.jsbmb.2018.07.003. Epub 2018 Jul 5.
• [5] Recessive ataxias.Handb Clin Neurol. 2018;155:73-89. doi: 10.1016/B978-0-444-64189-2.00005-6.
• [6] LINC complex alterations in DMD and EDMD/CMT fibroblasts.Eur J Cell Biol. 2012 Aug;91(8):614-28. doi: 10.1016/j.ejcb.2012.03.003. Epub 2012 May 1.
• [7] SUN2 Silencing Impairs CD4 T Cell Proliferation and Alters Sensitivity to HIV-1 Infection Independently of Cyclophilin A.J Virol. 2017 Feb 28;91(6):e02303-16. doi: 10.1128/JVI.02303-16. Print 2017 Mar 15.
• [8] SUN2: A potential therapeutic target in cancer.Oncol Lett. 2019 Feb;17(2):1401-1408. doi: 10.3892/ol.2018.9764. Epub 2018 Nov 27.
• [9] Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment.Histochem Cell Biol. 2012 Oct;138(4):643-51. doi: 10.1007/s00418-012-0977-5. Epub 2012 Jun 17.
• [10] Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.PLoS Genet. 2014 Sep 11;10(9):e1004605. doi: 10.1371/journal.pgen.1004605. eCollection 2014 Sep.
• [11] SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer.Sci Rep. 2015 Dec 10;5:17940. doi: 10.1038/srep17940.
• [12] Isolation of differentially expressed genes in human heart tissues.Biochim Biophys Acta. 2002 Dec 12;1588(3):241-6. doi: 10.1016/s0925-4439(02)00171-0.
• [13] 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.
• [14] 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.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] 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.
• [17] 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.
• [18] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [21] 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.
• [22] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [23] 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.
• [24] 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.