Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFW6WH7)

• DOT Name: Sp110 nuclear body protein (SP110)
• Synonyms: Interferon-induced protein 41/75; Speckled 110 kDa; Transcriptional coactivator Sp110
• Gene Name: SP110
• Related Disease:
  Hepatic veno-occlusive disease-immunodeficiency syndrome
  Small lymphocytic lymphoma
  Advanced cancer
  Cholangiocarcinoma
  Hepatic veno-occlusive disease
  Hepatitis B virus infection
  Immunodeficiency
  Latent tuberculosis infection
  Sclerosing cholangitis
  Severe combined immunodeficiency
  Extrapulmonary tuberculosis
• UniProt ID: SP110_HUMAN
• Pfam ID: PF03172 ; PF01342
• Sequence:
  MFTMTRAMEEALFQHFMHQKLGIAYAIHKPFPFFEGLLDNSIITKRMYMESLEACRNLIP
  VSRVVHNILTQLERTFNLSLLVTLFSQINLREYPNLVTIYRSFKRVGASYEWQSRDTPIL
  LEAPTGLAEGSSLHTPLALPPPQPPQPSCSPCAPRVSEPGTSSQQSDEILSESPSPSDPV
  LPLPALIQEGRSTSVTNDKLTSKMNAEEDSEEMPSLLTSTVQVASDNLIPQIRDKEDPQE
  MPHSPLGSMPEIRDNSPEPNDPEEPQEVSSTPSDKKGKKRKRCIWSTPKRRHKKKSLPGG
  TASSRHGIQKKLKRVDQVPQKKDDSTCNSTVETRAQKARTECARKSRSEEIIDGTSEMNE
  GKRSQKTPSTPRRVTQGAASPGHGIQEKLQVVDKVTQRKDDSTWNSEVMMRVQKARTKCA
  RKSRLKEKKKEKDICSSSKRRFQKNIHRRGKPKSDTVDFHCSKLPVTCGEAKGILYKKKM
  KHGSSVKCIRNEDGTWLTPNEFEVEGKGRNAKNWKRNIRCEGMTLGELLKRKNSDECEVC
  CQGGQLLCCGTCPRVFHEDCHIPPVEAKRMLWSCTFCRMKRSSGSQQCHHVSKTLERQMQ
  PQDQLIRDYGEPFQEAMWLDLVKERLITEMYTVAWFVRDMRLMFRNHKTFYKASDFGQVG
  LDLEAEFEKDLKDVLGFHEANDGGFWTLP
• Function: Transcription factor. May be a nuclear hormone receptor coactivator. Enhances transcription of genes with retinoic acid response elements (RARE).
• Tissue Specificity: Highly expressed in peripheral blood leukocytes and spleen. Detected at intermediate levels in thymus, prostate, testis, ovary, small intestine and colon, and at low levels in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatic veno-occlusive disease-immunodeficiency syndrome	DIS000H0	Definitive	Autosomal recessive	[1]
Small lymphocytic lymphoma	DIS30POX	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Cholangiocarcinoma	DIS71F6X	Strong	Genetic Variation	[4]
Hepatic veno-occlusive disease	DISAIU45	Strong	Genetic Variation	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[6]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[7]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[8]
Sclerosing cholangitis	DIS7GZNB	Strong	Genetic Variation	[4]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Genetic Variation	[9]
Extrapulmonary tuberculosis	DIS6KM28	moderate	Genetic Variation	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Sp110 nuclear body protein (SP110) decreases the response to substance of Cisplatin.	[28]
Daunorubicin	DMQUSBT	Approved	Sp110 nuclear body protein (SP110) affects the response to substance of Daunorubicin.	[29]

16 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 Sp110 nuclear body protein (SP110).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sp110 nuclear body protein (SP110).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sp110 nuclear body protein (SP110).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sp110 nuclear body protein (SP110).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sp110 nuclear body protein (SP110).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sp110 nuclear body protein (SP110).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sp110 nuclear body protein (SP110).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Sp110 nuclear body protein (SP110).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Sp110 nuclear body protein (SP110).	[19]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sp110 nuclear body protein (SP110).	[20]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Sp110 nuclear body protein (SP110).	[21]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Sp110 nuclear body protein (SP110).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sp110 nuclear body protein (SP110).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sp110 nuclear body protein (SP110).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sp110 nuclear body protein (SP110).	[26]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Sp110 nuclear body protein (SP110).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sp110 nuclear body protein (SP110).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sp110 nuclear body protein (SP110).	[25]

References

• [1] 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.
• [2] Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.Nat Commun. 2016 Mar 9;7:10933. doi: 10.1038/ncomms10933.
• [3] Expression Data Analysis for the Identification of Potential Biomarker of Pregnancy Associated Breast Cancer.Pathol Oncol Res. 2017 Jul;23(3):537-544. doi: 10.1007/s12253-016-0133-y. Epub 2016 Nov 10.
• [4] Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.Gut. 2018 Aug;67(8):1517-1524. doi: 10.1136/gutjnl-2016-313598. Epub 2017 Aug 4.
• [5] Clinical, molecular, and cellular immunologic findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome.J Allergy Clin Immunol. 2012 Sep;130(3):735-742.e6. doi: 10.1016/j.jaci.2012.02.054. Epub 2012 May 21.
• [6] Host transcription factor Speckled 110 kDa (Sp110), a nuclear body protein, is hijacked by hepatitis B virus protein X for viral persistence.J Biol Chem. 2017 Dec 15;292(50):20379-20393. doi: 10.1074/jbc.M117.796839. Epub 2017 Oct 18.
• [7] The role of hematopoietic stem cell transplantation in SP110 associated veno-occlusive disease with immunodeficiency syndrome.Pediatr Allergy Immunol. 2013 May;24(3):250-6. doi: 10.1111/pai.12051. Epub 2013 Mar 1.
• [8] Polymorphisms of SP110 are associated with both pulmonary and extra-pulmonary tuberculosis among the Vietnamese.PLoS One. 2014 Jul 9;9(7):e99496. doi: 10.1371/journal.pone.0099496. eCollection 2014.
• [9] Hepatic veno-occlusive disease with immunodeficiency (VODI): first reported case in the U.S. and identification of a unique mutation in Sp110.Clin Immunol. 2012 Nov;145(2):102-7. doi: 10.1016/j.clim.2012.07.016. Epub 2012 Aug 7.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [19] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [22] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [25] 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.
• [26] 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.
• [27] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [28] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.
• [29] Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007 Jun 1;67(11):5425-33. doi: 10.1158/0008-5472.CAN-06-4431.