Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP0107S)

DOT Name	Speckle-type POZ protein (SPOP)
Synonyms	HIB homolog 1; Roadkill homolog 1
Gene Name	SPOP
Related Disease	Adenocarcinoma ( ) Aerodigestive tract cancer ( ) B-cell lymphoma ( ) Benign prostatic hyperplasia ( ) Bone osteosarcoma ( ) Chromosomal disorder ( ) Colorectal carcinoma ( ) Endometrial cancer ( ) Endometrial carcinoma ( ) Epithelial ovarian cancer ( ) Familial prostate carcinoma ( ) Glioma ( ) Hepatocellular carcinoma ( ) Lung adenocarcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Lung neoplasm ( ) Neurodevelopmental disorder with microcephaly and dysmorphic facies ( ) Non-small-cell lung cancer ( ) Osteosarcoma ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Renal cell carcinoma ( ) Triple negative breast cancer ( ) Clear cell renal carcinoma ( ) Gastric cancer ( ) Kidney cancer ( ) Prostate adenocarcinoma ( ) Prostate neoplasm ( ) Renal carcinoma ( ) Stomach cancer ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Castration-resistant prostate carcinoma ( ) Chronic pancreatitis ( ) Endometrium neoplasm ( ) Liver cancer ( )
UniProt ID	SPOP_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2CR2; 3HQH; 3HQI; 3HQL; 3HQM; 3HSV; 3HTM; 3HU6; 3IVB; 3IVQ; 3IVV; 4EOZ; 4HS2; 4J8Z; 4O1V; 6F8F; 6F8G; 6I41; 6I5P; 6I68; 6I7A; 7D3D; 7KLZ; 7LIN; 7LIO; 7LIP; 7LIQ; 8DWS; 8DWT; 8DWU; 8DWV
Pfam ID	PF00651 ; PF00917
Sequence	MSRVPSPPPPAEMSSGPVAESWCYTQIKVVKFSYMWTINNFSFCREEMGEVIKSSTFSSG ANDKLKWCLRVNPKGLDEESKDYLSLYLLLVSCPKSEVRAKFKFSILNAKGEETKAMESQ RAYRFVQGKDWGFKKFIRRDFLLDEANGLLPDDKLTLFCEVSVVQDSVNISGQNTMNMVK VPECRLADELGGLWENSRFTDCCLCVAGQEFQAHKAILAARSPVFSAMFEHEMEESKKNR VEINDVEPEVFKEMMCFIYTGKAPNLDKMADDLLAAADKYALERLKVMCEDALCSNLSVE NAAEILILADLHSADQLKTQAVDFINYHASDVLETSGWKSMVVSHPHLVAEAYRSLASAQ CPFLGPPRKRLKQS
Function	Component of a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates the ubiquitination of target proteins, leading most often to their proteasomal degradation. In complex with CUL3, involved in ubiquitination and proteasomal degradation of BRMS1, DAXX, PDX1/IPF1, GLI2 and GLI3. In complex with CUL3, involved in ubiquitination of MACROH2A1 and BMI1; this does not lead to their proteasomal degradation. Inhibits transcriptional activation of PDX1/IPF1 targets, such as insulin, by promoting PDX1/IPF1 degradation. The cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOP has higher ubiquitin ligase activity than the complex that contains the heterodimer formed by SPOP and SPOPL. Involved in the regulation of bromodomain and extra-terminal motif (BET) proteins BRD2, BRD3, BRD4 stability. Plays an essential role for proper translation, but not for their degradation, of critical DNA replication licensing factors CDT1 and CDC6, thereby participating in DNA synthesis and cell proliferation. Regulates interferon regulatory factor 1/IRF1 proteasomal turnover by targeting S/T-rich degrons in IRF1. Facilitates the lysosome-dependent degradation of enterovirus EV71 protease 2A by inducing its 'Lys-48'-linked polyubiquitination, which ultimately restricts EV71 replication. Acts as an antiviral factor also against hepatitis B virus/HBV by promoting ubiquitination and subsequent degradation of HNF1A. In turn, inhibits HBV transcription and replication by preventing HNF1A stimulating activity of HBV preS1 promoter and enhancer II.
Tissue Specificity	Widely expressed.
KEGG Pathway	Hedgehog sig.ling pathway (hsa04340 )
Reactome Pathway	Hedgehog 'on' state (R-HSA-5632684 )

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adenocarcinoma	DIS3IHTY	Definitive	Genetic Variation	[1]
Aerodigestive tract cancer	DIS3AOQ7	Strong	Altered Expression	[2]
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[5]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[8]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[10]
Familial prostate carcinoma	DISL9KNO	Strong	Genetic Variation	[11]
Glioma	DIS5RPEH	Strong	Altered Expression	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[14]
Lung cancer	DISCM4YA	Strong	Altered Expression	[14]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[14]
Lung neoplasm	DISVARNB	Strong	Biomarker	[15]
Neurodevelopmental disorder with microcephaly and dysmorphic facies	DISHCZQ5	Strong	Autosomal dominant	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[16]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[17]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[18]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[2]
Gastric cancer	DISXGOUK	moderate	Biomarker	[19]
Kidney cancer	DISBIPKM	moderate	Genetic Variation	[9]
Prostate adenocarcinoma	DISBZYU8	moderate	Biomarker	[20]
Prostate neoplasm	DISHDKGQ	moderate	Genetic Variation	[21]
Renal carcinoma	DISER9XT	moderate	Genetic Variation	[9]
Stomach cancer	DISKIJSX	moderate	Biomarker	[19]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[22]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Genetic Variation	[23]
Chronic pancreatitis	DISBUOMJ	Limited	Biomarker	[24]
Endometrium neoplasm	DIS6OS2L	Limited	Biomarker	[25]
Liver cancer	DISDE4BI	Limited	Biomarker	[22]
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⏷ Show the Full List of 36 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

4 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 Speckle-type POZ protein (SPOP).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Speckle-type POZ protein (SPOP).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Speckle-type POZ protein (SPOP).	[31]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Speckle-type POZ protein (SPOP).	[32]
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3 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 Speckle-type POZ protein (SPOP).	[28]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Speckle-type POZ protein (SPOP).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Speckle-type POZ protein (SPOP).	[30]
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References

1	Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer.Cancer Res. 2014 Oct 1;74(19):5631-43. doi: 10.1158/0008-5472.CAN-14-0476.
2	The association of speckle-type POZ protein with lymph node metastasis and prognosis in cancer patients: A meta-analysis.Medicine (Baltimore). 2019 Oct;98(40):e17439. doi: 10.1097/MD.0000000000017439.
3	CRL3-SPOP ubiquitin ligase complex suppresses the growth of diffuse large B-cell lymphoma by negatively regulating the MyD88/NF-B signaling.Leukemia. 2020 May;34(5):1305-1314. doi: 10.1038/s41375-019-0661-z. Epub 2019 Nov 27.
4	Potential Prognostic Role for SPOP, DAXX, RARRES1, and LAMP2 as an Autophagy Related Genes in Prostate Cancer.Urol J. 2020 Mar 16;17(2):156-163. doi: 10.22037/uj.v0i0.4935.
5	SPOP suppresses osteosarcoma invasion via PI3K/AKT/NF-B signaling pathway.Eur Rev Med Pharmacol Sci. 2018 Feb;22(3):609-615. doi: 10.26355/eurrev_201802_14275.
6	Speckle-type POZ protein, SPOP, is involved in the DNA damage response.Carcinogenesis. 2014 Aug;35(8):1691-7. doi: 10.1093/carcin/bgu022. Epub 2014 Jan 22.
7	ILF3 is a substrate of SPOP for regulating serine biosynthesis in colorectal cancer.Cell Res. 2020 Feb;30(2):163-178. doi: 10.1038/s41422-019-0257-1. Epub 2019 Nov 26.
8	Uterine function in the mouse requires speckle-type poz protein.Biol Reprod. 2018 Jun 1;98(6):856-869. doi: 10.1093/biolre/ioy060.
9	The ubiquitin ligase adaptor SPOP in cancer.FEBS J. 2019 Oct;286(20):3946-3958. doi: 10.1111/febs.15056. Epub 2019 Sep 18.
10	SPOP Regulates The Biological Mechanism Of Ovarian Cancer Cells Through The Hh Signaling Pathway.Onco Targets Ther. 2019 Nov 6;12:9239-9248. doi: 10.2147/OTT.S215940. eCollection 2019.
11	Identification of a novel germline SPOP mutation in a family with hereditary prostate cancer. Prostate. 2014 Jun;74(9):983-90. doi: 10.1002/pros.22818. Epub 2014 May 6.
12	Decreased expression of the SPOP gene is associated with poor prognosis in glioma.Int J Oncol. 2015 Jan;46(1):333-41. doi: 10.3892/ijo.2014.2729. Epub 2014 Oct 24.
13	Speckle-type POZ protein suppresses hepatocellular carcinoma cell migration and invasion via ubiquitin-dependent proteolysis of SUMO1/sentrin specific peptidase 7.Biochem Biophys Res Commun. 2018 Jul 7;502(1):30-42. doi: 10.1016/j.bbrc.2018.05.115. Epub 2018 May 24.
14	SPOP regulates the DNA damage response and lung adenocarcinoma cell response to radiation.Am J Cancer Res. 2019 Jul 1;9(7):1469-1483. eCollection 2019.
15	SPOP promotes SIRT2 degradation and suppresses non-small cell lung cancer cell growth.Biochem Biophys Res Commun. 2017 Feb 5;483(2):880-884. doi: 10.1016/j.bbrc.2017.01.027. Epub 2017 Jan 7.
16	MiR-520b promotes the progression of non-small cell lung cancer through activating Hedgehog pathway.J Cell Mol Med. 2019 Jan;23(1):205-215. doi: 10.1111/jcmm.13909. Epub 2018 Nov 8.
17	Speckle-type POZ protein as a diagnostic biomarker in renal cell carcinoma.J Cancer Res Ther. 2018 Jul-Sep;14(5):977-982. doi: 10.4103/jcrt.JCRT_942_15.
18	LINC01638 lncRNA activates MTDH-Twist1 signaling by preventing SPOP-mediated c-Myc degradation in triple-negative breast cancer.Oncogene. 2018 Nov;37(47):6166-6179. doi: 10.1038/s41388-018-0396-8. Epub 2018 Jul 12.
19	miRNA-543 promotes cell migration and invasion by targeting SPOP in gastric cancer.Onco Targets Ther. 2018 Aug 21;11:5075-5082. doi: 10.2147/OTT.S161316. eCollection 2018.
20	SPOP regulates prostate epithelial cell proliferation and promotes ubiquitination and turnover of c-MYC oncoprotein.Oncogene. 2017 Aug 17;36(33):4767-4777. doi: 10.1038/onc.2017.80. Epub 2017 Apr 17.
21	SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG-rearranged prostate cancer.Prostate. 2019 Jul;79(10):1156-1165. doi: 10.1002/pros.23830. Epub 2019 May 15.
22	Speckle-type POZ protein is negatively associated with malignancies and inhibits cell proliferation and migration in liver cancer.Tumour Biol. 2015 Dec;36(12):9753-61. doi: 10.1007/s13277-015-3753-z. Epub 2015 Jul 10.
23	TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer.Cancer Cell. 2016 Jun 13;29(6):846-858. doi: 10.1016/j.ccell.2016.04.012. Epub 2016 May 26.
24	SPOP inhibits mice pancreatic stellate cell activation by promoting FADD degradation in cerulein-induced chronic pancreatitis.Exp Cell Res. 2019 Nov 1;384(1):111606. doi: 10.1016/j.yexcr.2019.111606. Epub 2019 Sep 4.
25	Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes.Nat Genet. 2012 Dec;44(12):1310-5. doi: 10.1038/ng.2455. Epub 2012 Oct 28.
26	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.
27	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.
28	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.
29	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.
30	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.
31	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.
32	Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.