Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Y5CC3)

DOT Name	26S proteasome non-ATPase regulatory subunit 9 (PSMD9)
Synonyms	26S proteasome regulatory subunit p27
Gene Name	PSMD9
Related Disease	Multiple endocrine neoplasia type 1 ( ) Adenoma ( ) B-cell neoplasm ( ) Bladder cancer ( ) Bone osteosarcoma ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Colon cancer ( ) Depression ( ) Endometrial carcinoma ( ) Epithelial ovarian cancer ( ) Gastrointestinal stromal tumour ( ) Glioblastoma multiforme ( ) Glioma ( ) Hepatocellular carcinoma ( ) High blood pressure ( ) Lung cancer ( ) Lung carcinoma ( ) Mantle cell lymphoma ( ) Metastatic malignant neoplasm ( ) Nephropathy ( ) Neuroblastoma ( ) Non-insulin dependent diabetes ( ) Non-small-cell lung cancer ( ) Obesity ( ) Osteosarcoma ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Plasma cell myeloma ( ) Renal cell carcinoma ( ) Small lymphocytic lymphoma ( ) Thyroid tumor ( ) Triple negative breast cancer ( ) Type-1/2 diabetes ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Acute myelogenous leukaemia ( ) Adult glioblastoma ( ) Liver cirrhosis ( ) Esophageal squamous cell carcinoma ( ) Melanoma ( ) Thyroid gland carcinoma ( ) Carcinoma ( ) Clear cell renal carcinoma ( ) Colon carcinoma ( ) leukaemia ( ) Leukemia ( ) Liver cancer ( ) Nasopharyngeal carcinoma ( )
UniProt ID	PSMD9_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF18265 ; PF17820
Sequence	MSDEEARQSGGSSQAGVVTVSDVQELMRRKEEIEAQIKANYDVLESQKGIGMNEPLVDCE GYPRSDVDLYQVRTARHNIICLQNDHKAVMKQVEEALHQLHARDKEKQARDMAEAHKEAM SRKLGQSESQGPPRAFAKVNSISPGSPASIAGLQVDDEIVEFGSVNTQNFQSLHNIGSVV QHSEGKPLNVTVIRRGEKHQLRLVPTRWAGKGLLGCNIIPLQR
Function	Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.
Tissue Specificity	Expressed in all tissues tested, highly expressed in liver and kidney.
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 )
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

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Multiple endocrine neoplasia type 1	DIS0RJRK	Definitive	Genetic Variation	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Bone osteosarcoma	DIST1004	Strong	Posttranslational Modification	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Depression	DIS3XJ69	Strong	Genetic Variation	[8]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[12]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
High blood pressure	DISY2OHH	Strong	Altered Expression	[15]
Lung cancer	DISCM4YA	Strong	Altered Expression	[16]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[16]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[18]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[8]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[19]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[20]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[21]
Obesity	DIS47Y1K	Strong	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Strong	Posttranslational Modification	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Plasma cell myeloma	DIS0DFZ0	Strong	Posttranslational Modification	[22]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[23]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[24]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[25]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[26]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[27]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
Acute myelogenous leukaemia	DISCSPTN	moderate	Altered Expression	[28]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[12]
Liver cirrhosis	DIS4G1GX	moderate	Biomarker	[29]
Esophageal squamous cell carcinoma	DIS5N2GV	Disputed	Altered Expression	[30]
Melanoma	DIS1RRCY	Disputed	Biomarker	[31]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Biomarker	[25]
Carcinoma	DISH9F1N	Limited	Biomarker	[32]
Clear cell renal carcinoma	DISBXRFJ	Limited	Altered Expression	[23]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[7]
leukaemia	DISS7D1V	Limited	Biomarker	[33]
Leukemia	DISNAKFL	Limited	Biomarker	[33]
Liver cancer	DISDE4BI	Limited	Altered Expression	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[34]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

8 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 26S proteasome non-ATPase regulatory subunit 9 (PSMD9).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9).	[36]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9).	[37]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9).	[38]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9).	[39]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9).	[41]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9).	[42]
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⏷ Show the Full List of 8 Drug(s)

References

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8	T2D and Depression Risk Gene Proteasome Modulator 9 is Linked to Insomnia.Sci Rep. 2015 Jul 13;5:12032. doi: 10.1038/srep12032.
9	Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity.Curr Mol Med. 2016;16(3):252-65. doi: 10.2174/1566524016666160225153307.
10	Cell Cycle Regulator p27 Mediates Body Mass Index Effects in Ovarian Cancer in FIGO-stages I-II.Cancer Genomics Proteomics. 2019 Nov-Dec;16(6):443-450. doi: 10.21873/cgp.20148.
11	Cyclin D1 is a mediator of gastrointestinal stromal tumor KIT-independence.Oncogene. 2019 Sep;38(39):6615-6629. doi: 10.1038/s41388-019-0894-3. Epub 2019 Aug 1.
12	PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells.Int J Cancer. 2016 Jul 1;139(1):99-111. doi: 10.1002/ijc.30041. Epub 2016 Mar 2.
13	TRIM44 is indispensable for glioma cell proliferation and cell cycle progression through AKT/p21/p27 signaling pathway.J Neurooncol. 2019 Nov;145(2):211-222. doi: 10.1007/s11060-019-03301-0. Epub 2019 Oct 11.
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16	Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer.Int J Mol Sci. 2016 Mar 24;17(4):437. doi: 10.3390/ijms17040437.
17	Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma.J Cell Commun Signal. 2019 Sep;13(3):421-434. doi: 10.1007/s12079-018-0494-y. Epub 2018 Nov 21.
18	Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation.Oncogene. 2015 Oct;34(43):5447-59. doi: 10.1038/onc.2014.473. Epub 2015 Feb 16.
19	TIPE? suppresses growth and aggressiveness of hepatocellular carcinoma cells through downregulation of the phosphoinositide 3kinase/AKT signaling pathway.Mol Med Rep. 2018 May;17(5):7017-7026. doi: 10.3892/mmr.2018.8789. Epub 2018 Mar 20.
20	Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome.Am J Med Genet B Neuropsychiatr Genet. 2019 Apr;180(3):186-203. doi: 10.1002/ajmg.b.32712. Epub 2019 Feb 6.
21	Cytoplasmic p27(Kip1) promotes tumorigenesis via suppression of RhoB activity.J Pathol. 2019 Jan;247(1):60-71. doi: 10.1002/path.5167. Epub 2018 Dec 11.
22	ADP-ribosylation factor 1 (ARF1) takes part in cell proliferation and cell adhesion-mediated drug resistance (CAM-DR).Ann Hematol. 2017 May;96(5):847-858. doi: 10.1007/s00277-017-2949-2. Epub 2017 Feb 25.
23	The long noncoding RNA KCNQ1DN suppresses the survival of renal cell carcinoma cells through downregulating c-Myc.J Cancer. 2019 Aug 19;10(19):4662-4670. doi: 10.7150/jca.29280. eCollection 2019.
24	High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle.Oncotarget. 2014 Jul 15;5(13):4694-708. doi: 10.18632/oncotarget.2100.
25	Rewiring of the apoptotic TGF--SMAD/NFB pathway through an oncogenic function of p27 in human papillary thyroid cancer.Oncogene. 2017 Feb 2;36(5):652-666. doi: 10.1038/onc.2016.233. Epub 2016 Jul 25.
26	Role of mitochondria in rescuing glycolytically inhibited subpopulation of triple negative but not hormone-responsive breast cancer cells.Sci Rep. 2019 Sep 24;9(1):13748. doi: 10.1038/s41598-019-50141-z.
27	Proteasome modulator 9 and macrovascular pathology of T2D.Cardiovasc Diabetol. 2011 Apr 17;10:32. doi: 10.1186/1475-2840-10-32.
28	c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor.J Cell Biochem. 2008 Aug 15;104(6):2091-106. doi: 10.1002/jcb.21765.
29	miR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients.Biochem Biophys Res Commun. 2012 Apr 27;421(1):4-8. doi: 10.1016/j.bbrc.2012.03.025. Epub 2012 Mar 13.
30	Targeted therapy of the AKT kinase inhibits esophageal squamous cell carcinoma growth in vitro and in vivo.Int J Cancer. 2019 Aug 15;145(4):1007-1019. doi: 10.1002/ijc.32285. Epub 2019 Apr 3.
31	Loss of tumor suppressors KAI1 and p27 identifies a unique subgroup of primary melanoma patients with poor prognosis.Oncotarget. 2015 Sep 8;6(26):23026-35. doi: 10.18632/oncotarget.4854.
32	Predictive value of FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas: a retrospective study.Clin Oral Investig. 2019 Oct;23(10):3801-3809. doi: 10.1007/s00784-019-02809-z. Epub 2019 Jan 23.
33	CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27(kip1) signaling.Haematologica. 2017 Apr;102(4):707-718. doi: 10.3324/haematol.2016.151555. Epub 2017 Jan 25.
34	Cyclin-Dependent Kinase Inhibitor 3 Promotes Cancer Cell Proliferation and Tumorigenesis in Nasopharyngeal Carcinoma by Targeting p27.Oncol Res. 2017 Nov 2;25(9):1431-1440. doi: 10.3727/096504017X14835311718295. Epub 2017 Jan 20.
35	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
36	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.
37	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.
38	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
39	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.
40	Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
41	Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
42	Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs. Int J Mol Sci. 2015 Nov 26;16(12):28169-79. doi: 10.3390/ijms161226089.