Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY6X27P)

DOT Name	26S proteasome non-ATPase regulatory subunit 8 (PSMD8)
Synonyms	26S proteasome regulatory subunit RPN12; 26S proteasome regulatory subunit S14; p31
Gene Name	PSMD8
Related Disease	Neoplasm ( ) Acquired immune deficiency syndrome ( ) Advanced cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Carcinoma ( ) Hepatitis B virus infection ( ) Hepatocellular carcinoma ( ) HIV infectious disease ( ) Liposarcoma ( ) Lung cancer ( ) Lung carcinoma ( ) Mesothelioma ( ) Non-small-cell lung cancer ( ) Nasopharyngeal carcinoma ( ) Thyroid gland papillary carcinoma ( ) Type-1 diabetes ( )
UniProt ID	PSMD8_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5GJQ ; 5GJR ; 5L4K ; 5LN3 ; 5M32 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFP ; 5VFQ ; 5VFR ; 5VFS ; 5VFT ; 5VFU ; 5VGZ ; 5VHF ; 5VHH ; 5VHI ; 5VHS ; 6MSB ; 6MSD ; 6MSG ; 6MSH ; 6MSJ ; 6MSK ; 6WJD ; 6WJN ; 7QXN ; 7QXP ; 7QXU ; 7QXW ; 7QXX ; 7QY7 ; 7QYA ; 7QYB ; 7W37 ; 7W38 ; 7W39 ; 7W3A ; 7W3B ; 7W3C ; 7W3F ; 7W3G ; 7W3H ; 7W3I ; 7W3J ; 7W3K ; 7W3M ; 8CVT
Pfam ID	PF10075
Sequence	MFIKGRAPRAPPRERRRATRGGLRQVVAPPRALGSTSRPHFRRASVCRRRCRKSGGLLAA SRKMAAAAVNGAAGFSSSGPAATSGAVLQAATGMYEQLKGEWNRKSPNLSKCGEELGRLK LVLLELNFLPTTGTKLTKQQLILARDILEIGAQWSILRKDIPSFERYMAQLKCYYFDYKE QLPESAYMHQLLGLNLLFLLSQNRVAEFHTELERLPAKDIQTNVYIKHPVSLEQYLMEGS YNKVFLAKGNIPAESYTFFIDILLDTIRDEIAGCIEKAYEKILFTEATRILFFNTPKKMT DYAKKRGWVLGPNNYYSFASQQQKPEDTTIPSTELAKQVIEYARQLEMIV
Function	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.
KEGG Pathway	Proteasome (hsa03050 ) Alzheimer disease (hsa05010 ) Parkinson disease (hsa05012 ) Amyotrophic lateral sclerosis (hsa05014 ) Huntington disease (hsa05016 ) Spinocerebellar ataxia (hsa05017 ) Prion disease (hsa05020 ) Pathways of neurodegeneration - multiple diseases (hsa05022 ) Epstein-Barr virus infection (hsa05169 )
Reactome Pathway	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176 ) ER-Phagosome pathway (R-HSA-1236974 ) Cross-presentation of soluble exogenous antigens (endosomes) (R-HSA-1236978 ) Autodegradation of Cdh1 by Cdh1 (R-HSA-174084 ) SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113 ) APC/C (R-HSA-174154 ) APC/C (R-HSA-174178 ) Cdc20 (R-HSA-174184 ) Vpu mediated degradation of CD4 (R-HSA-180534 ) Vif-mediated degradation of APOBEC3G (R-HSA-180585 ) SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577 ) Degradation of beta-catenin by the destruction complex (R-HSA-195253 ) Downstream TCR signaling (R-HSA-202424 ) Regulation of activated PAK-2p34 by proteasome mediated degradation (R-HSA-211733 ) Separation of Sister Chromatids (R-HSA-2467813 ) FCERI mediated NF-kB activation (R-HSA-2871837 ) Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425 ) Regulation of ornithine decarboxylase (ODC) (R-HSA-350562 ) ABC-family proteins mediated transport (R-HSA-382556 ) AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408 ) Asymmetric localization of PCP proteins (R-HSA-4608870 ) Degradation of AXIN (R-HSA-4641257 ) Degradation of DVL (R-HSA-4641258 ) Hedgehog ligand biogenesis (R-HSA-5358346 ) Hh mutants are degraded by ERAD (R-HSA-5362768 ) Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761 ) CLEC7A (Dectin-1) signaling (R-HSA-5607764 ) Degradation of GLI1 by the proteasome (R-HSA-5610780 ) Degradation of GLI2 by the proteasome (R-HSA-5610783 ) GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785 ) Hedgehog 'on' state (R-HSA-5632684 ) Regulation of RAS by GAPs (R-HSA-5658442 ) TNFR2 non-canonical NF-kB pathway (R-HSA-5668541 ) NIK-->noncanonical NF-kB signaling (R-HSA-5676590 ) Defective CFTR causes cystic fibrosis (R-HSA-5678895 ) MAPK6/MAPK4 signaling (R-HSA-5687128 ) UCH proteinases (R-HSA-5689603 ) Ub-specific processing proteases (R-HSA-5689880 ) Assembly of the pre-replicative complex (R-HSA-68867 ) Orc1 removal from chromatin (R-HSA-68949 ) CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017 ) G2/M Checkpoints (R-HSA-69481 ) Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601 ) Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815 ) The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276 ) FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050 ) RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236 ) Regulation of RUNX2 expression and activity (R-HSA-8939902 ) Regulation of RUNX3 expression and activity (R-HSA-8941858 ) Regulation of PTEN stability and activity (R-HSA-8948751 ) Neddylation (R-HSA-8951664 ) Regulation of expression of SLITs and ROBOs (R-HSA-9010553 ) Interleukin-1 signaling (R-HSA-9020702 ) Negative regulation of NOTCH4 signaling (R-HSA-9604323 ) KEAP1-NFE2L2 pathway (R-HSA-9755511 ) GSK3B and BTRC (R-HSA-9762114 ) Somitogenesis (R-HSA-9824272 ) Antigen processing (R-HSA-983168 ) Activation of NF-kappaB in B cells (R-HSA-1169091 )

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Acquired immune deficiency syndrome	DISL5UOX	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
HIV infectious disease	DISO97HC	Strong	Biomarker	[8]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Mesothelioma	DISKWK9M	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[11]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[12]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[13]
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⏷ Show the Full List of 18 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[19]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[20]
Marinol	DM70IK5	Approved	Marinol decreases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[21]
Selenium	DM25CGV	Approved	Selenium increases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[22]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[25]
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⏷ Show the Full List of 10 Drug(s)

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 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 26S proteasome non-ATPase regulatory subunit 8 (PSMD8).	[23]
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References

1	Downregulation of NOB1 suppresses the proliferation and tumor growth of non-small cell lung cancer in vitro and in vivo.Oncol Rep. 2014 Mar;31(3):1271-6. doi: 10.3892/or.2014.2991. Epub 2014 Jan 21.
2	An HTLV-III peptide produced by recombinant DNA is immunoreactive with sera from patients with AIDS.Nature. 1985 May 9-15;315(6015):151-4. doi: 10.1038/315151a0.
3	Epstein-Barr virus gene expression in human breast cancer: protagonist or passenger?.Br J Cancer. 2003 Jul 7;89(1):113-9. doi: 10.1038/sj.bjc.6601027.
4	Conjugated linoleic acid (CLA) inhibits expression of the Spot 14 (THRSP) and fatty acid synthase genes and impairs the growth of human breast cancer and liposarcoma cells.Nutr Cancer. 2009;61(1):114-22. doi: 10.1080/01635580802348666.
5	S14 protein in breast cancer cells: direct evidence of regulation by SREBP-1c, superinduction with progestin, and effects on cell growth.Exp Cell Res. 2006 Feb 1;312(3):278-88. doi: 10.1016/j.yexcr.2005.10.022. Epub 2005 Nov 21.
6	Polypeptides coded for by the region pre-S and gene S of hepatitis B virus DNA with the receptor for polymerized human serum albumin: expression on hepatitis B particles produced in the HBeAg or anti-HBe phase of hepatitis B virus infection.J Immunol. 1986 May 1;136(9):3467-72.
7	Downregulation of NIN/RPN12 binding protein inhibit the growth of human hepatocellular carcinoma cells.Mol Biol Rep. 2012 Jan;39(1):501-7. doi: 10.1007/s11033-011-0764-8. Epub 2011 May 15.
8	Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
9	Synergistic anticancer activity of arsenic trioxide with erlotinib is based on inhibition of EGFR-mediated DNA double-strand break repair.Mol Cancer Ther. 2013 Jun;12(6):1073-84. doi: 10.1158/1535-7163.MCT-13-0065. Epub 2013 Apr 2.
10	Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells.Oncotarget. 2017 Oct 16;8(55):94711-94725. doi: 10.18632/oncotarget.21885. eCollection 2017 Nov 7.
11	Expression of BARF1 gene encoded by Epstein-Barr virus in nasopharyngeal carcinoma biopsies.Cancer Res. 2000 Oct 1;60(19):5584-8.
12	Expression of the NOB1 gene and its clinical significance in papillary thyroid carcinoma.J Int Med Res. 2013 Jun;41(3):568-72. doi: 10.1177/0300060513479862. Epub 2013 May 17.
13	Prevention of Type 1 Diabetes with Acetalated Dextran Microparticles Containing Rapamycin and Pancreatic Peptide P31.Adv Healthc Mater. 2018 Sep;7(18):e1800341. doi: 10.1002/adhm.201800341. Epub 2018 Jul 26.
14	Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
15	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.
16	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
17	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.
18	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.
19	Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
20	Evaluation of early biomarkers of muscle anabolic response to testosterone. J Cachexia Sarcopenia Muscle. 2011 Mar;2(1):45-56. doi: 10.1007/s13539-011-0021-y. Epub 2011 Feb 26.
21	JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
22	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.
23	Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
24	Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem. 2020 Jan 31;295(5):1271-1287. doi: 10.1074/jbc.RA119.011174. Epub 2019 Dec 5.
25	Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.