Details of Drug Off-Target (DOT)

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

• DOT Name: Cyclin-dependent kinases regulatory subunit 1 (CKS1B)
• Synonyms: CKS-1
• Gene Name: CKS1B
• Related Disease:
  Melanocytic nevus
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Burkitt lymphoma
  Carcinoma
  Carcinoma of esophagus
  Carcinoma of liver and intrahepatic biliary tract
  Cholangiocarcinoma
  Chromosomal disorder
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Endometriosis
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Liver cancer
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Nasopharyngeal carcinoma
  Neoplasm
  Neoplasm of esophagus
  Plasma cell myeloma
  Precancerous condition
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Seminoma
  Squamous cell carcinoma
  Transitional cell carcinoma
  Urothelial carcinoma
  Adult lymphoma
  Lymphoma
  Pediatric lymphoma
  Retinoblastoma
  Acute lymphocytic leukaemia
  Childhood acute lymphoblastic leukemia
  Cutaneous squamous cell carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Melanoma
  Non-small-cell lung cancer
  T-cell acute lymphoblastic leukaemia
• UniProt ID: CKS1_HUMAN
• PDB ID: 1BUH; 1DKS; 1DKT; 2ASS; 2AST; 4YC6; 7B5L; 7B5M; 7B5R; 7NJ0; 8BYA; 8BYL; 8OR0; 8OR4
• Pfam ID: PF01111
• Sequence:
  MSHKQIYYSDKYDDEEFEYRHVMLPKDIAKLVPKTHLMSESEWRNLGVQQSQGWVHYMIH
  EPEPHILLFRRPLPKKPKK
• Function: Binds to the catalytic subunit of the cyclin dependent kinases and is essential for their biological function.
• KEGG Pathway:
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Cyclin D associated events in G1 (R-HSA-69231)
  SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanocytic nevus	DISYS32D	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[7]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[8]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Altered Expression	[10]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[11]
Endometriosis	DISX1AG8	Strong	Altered Expression	[12]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[13]
Liver cancer	DISDE4BI	Strong	Biomarker	[14]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[15]
Lung cancer	DISCM4YA	Strong	Altered Expression	[16]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[16]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[17]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[13]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[2]
Precancerous condition	DISV06FL	Strong	Biomarker	[18]
Prostate cancer	DISF190Y	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[19]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[20]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[21]
Seminoma	DIS3J8LJ	Strong	Biomarker	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[17]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[23]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[23]
Adult lymphoma	DISK8IZR	moderate	Biomarker	[18]
Lymphoma	DISN6V4S	moderate	Biomarker	[18]
Pediatric lymphoma	DIS51BK2	moderate	Biomarker	[18]
Retinoblastoma	DISVPNPB	moderate	Altered Expression	[2]
Acute lymphocytic leukaemia	DISPX75S	Limited	Biomarker	[24]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Biomarker	[24]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[25]
Endometrial cancer	DISW0LMR	Limited	Biomarker	[26]
Endometrial carcinoma	DISXR5CY	Limited	Biomarker	[26]
Melanoma	DIS1RRCY	Limited	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[27]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Altered Expression	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[30]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[31]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[32]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[33]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[34]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[35]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[35]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[37]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[38]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[39]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[40]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[41]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[42]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[43]
Fluoxetine	DM3PD2C	Approved	Fluoxetine decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[44]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[45]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[46]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[48]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[49]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[50]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Cyclin-dependent kinases regulatory subunit 1 (CKS1B).	[36]

References

• [1] CKS1 expression in melanocytic nevi and melanoma.Oncotarget. 2017 Dec 23;9(3):4173-4187. doi: 10.18632/oncotarget.23648. eCollection 2018 Jan 9.
• [2] Downregulation of CKS1B restrains the proliferation, migration, invasion and angiogenesis of retinoblastoma cells through the MEK/ERK signaling pathway.Int J Mol Med. 2019 Jul;44(1):103-114. doi: 10.3892/ijmm.2019.4183. Epub 2019 May 8.
• [3] Regulation of Transient Site-specific Copy Gain by MicroRNA.J Biol Chem. 2016 Mar 4;291(10):4862-71. doi: 10.1074/jbc.M115.711648. Epub 2016 Jan 11.
• [4] Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis.EMBO J. 2007 May 16;26(10):2562-74. doi: 10.1038/sj.emboj.7601691. Epub 2007 Apr 26.
• [5] Increased expression of Cks1 protein is associated with lymph node metastasis and poor prognosis in nasopharyngeal carcinoma.Diagn Pathol. 2017 Jan 7;12(1):2. doi: 10.1186/s13000-016-0589-9.
• [6] Long noncoding RNA MALAT1 affects the efficacy of radiotherapy for esophageal squamous cell carcinoma by regulating Cks1 expression.J Oral Pathol Med. 2017 Sep;46(8):583-590. doi: 10.1111/jop.12538. Epub 2017 Jun 5.
• [7] Loss of miR-1258 contributes to carcinogenesis and progression of liver cancer through targeting CDC28 protein kinase regulatory subunit 1B.Oncotarget. 2016 Jul 12;7(28):43419-43431. doi: 10.18632/oncotarget.9728.
• [8] Apoptosis-related protein-1 acts as a tumor suppressor in cholangiocarcinoma cells by inducing cell cycle arrest via downregulation of cyclin-dependent kinase subunits.Oncol Rep. 2016 Feb;35(2):809-16. doi: 10.3892/or.2015.4422. Epub 2015 Nov 16.
• [9] Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation.Biol Blood Marrow Transplant. 2016 Dec;22(12):2159-2164. doi: 10.1016/j.bbmt.2016.09.003. Epub 2016 Sep 13.
• [10] PADI3 plays an antitumor role via the Hsp90/CKS1 pathway in colon cancer.Cancer Cell Int. 2019 Nov 5;19:277. doi: 10.1186/s12935-019-0999-3. eCollection 2019.
• [11] The prognostic role of Skp2 and the tumor suppressor protein p27 in colorectal cancer.J BUON. 2017 Sep-Oct;22(5):1122-1130.
• [12] Cumulative alterations of p27-related cell-cycle regulators in the development of endometriosis-associated ovarian clear cell adenocarcinoma.Histopathology. 2010 May;56(6):740-9. doi: 10.1111/j.1365-2559.2010.03551.x.
• [13] Cks1 regulates human hepatocellular carcinoma cell progression through osteopontin expression.Biochem Biophys Res Commun. 2019 Jan 1;508(1):275-281. doi: 10.1016/j.bbrc.2018.11.070. Epub 2018 Nov 26.
• [14] A Synthetic Dosage Lethal Genetic Interaction Between CKS1B and PLK1 Is Conserved in Yeast and Human Cancer Cells.Genetics. 2016 Oct;204(2):807-819. doi: 10.1534/genetics.116.190231. Epub 2016 Aug 24.
• [15] Clinical significance and expression of cyclin kinase subunits 1 and 2 in hepatocellular carcinoma.Liver Int. 2010 Jan;30(1):119-25. doi: 10.1111/j.1478-3231.2009.02106.x. Epub 2009 Oct 21.
• [16] 3-O-(Z)-coumaroyloleanolic acid overcomes Cks1b-induced chemoresistance in lung cancer by inhibiting Hsp90 and MEK pathways.Biochem Pharmacol. 2017 Jul 1;135:35-49. doi: 10.1016/j.bcp.2017.03.007. Epub 2017 Mar 11.
• [17] CDC28 protein kinase regulatory subunit 1B (CKS1B) expression and genetic status analysis in oral squamous cell carcinoma.Histol Histopathol. 2011 Jan;26(1):71-7. doi: 10.14670/HH-26.71.
• [18] EBV latent membrane protein 2A orchestrates p27(kip1) degradation via Cks1 to accelerate MYC-driven lymphoma in mice.Blood. 2017 Dec 7;130(23):2516-2526. doi: 10.1182/blood-2017-07-796821. Epub 2017 Oct 26.
• [19] p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer.Oncogene. 2017 Jan 5;36(1):60-70. doi: 10.1038/onc.2016.175. Epub 2016 May 16.
• [20] Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death.Int J Cancer. 2008 Aug 1;123(3):543-51. doi: 10.1002/ijc.23548.
• [21] Prognostic implication of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma: a tissue microarray study.J Exp Clin Cancer Res. 2008 Oct 15;27(1):51. doi: 10.1186/1756-9966-27-51.
• [22] Altered expression of p27(Kip1) -interacting cell-cycle regulators in the adult testicular germ cell tumors: potential role in tumor development and histological progression.APMIS. 2012 Nov;120(11):890-900. doi: 10.1111/j.1600-0463.2012.02919.x. Epub 2012 May 24.
• [23] Increased SKP2 and CKS1 gene expression contributes to the progression of human urothelial carcinoma.J Urol. 2007 Jul;178(1):301-7. doi: 10.1016/j.juro.2007.03.002. Epub 2007 May 17.
• [24] ckshs expression is linked to cell proliferation in normal and malignant human lymphoid cells.Int J Cancer. 1999 Jul 2;82(1):98-104. doi: 10.1002/(sici)1097-0215(19990702)82:1<98::aid-ijc17>3.0.co;2-a.
• [25] CKS1B amplification is a frequent event in cutaneous squamous cell carcinoma with aggressive clinical behaviour.Genes Chromosomes Cancer. 2010 Nov;49(11):1054-61. doi: 10.1002/gcc.20814.
• [26] TGF- activates APC through Cdh1 binding for Cks1 and Skp2 proteasomal destruction stabilizing p27kip1 for normal endometrial growth.Cell Cycle. 2016;15(7):931-47. doi: 10.1080/15384101.2016.1150393.
• [27] High expression of Cks1 in human non-small cell lung carcinomas.Biochem Biophys Res Commun. 2003 Apr 11;303(3):978-84. doi: 10.1016/s0006-291x(03)00469-8.
• [28] 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.
• [29] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [30] 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.
• [31] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [32] 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.
• [33] Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene. 2001 Jan 10;262(1-2):207-14. doi: 10.1016/s0378-1119(00)00530-8.
• [34] 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.
• [35] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [36] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [37] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [38] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [39] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [40] DNA array analysis of the effects of aspirin on colon cancer cells: involvement of Rac1. Carcinogenesis. 2004 Jul;25(7):1293-8.
• [41] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [42] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [43] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [44] Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS)1. Biochem Pharmacol. 2008 May 15;75(10):1924-34. doi: 10.1016/j.bcp.2008.02.013. Epub 2008 Feb 17.
• [45] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [46] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [47] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [48] MCM-2 is a therapeutic target of Trichostatin A in colon cancer cells. Toxicol Lett. 2013 Jul 31;221(1):23-30. doi: 10.1016/j.toxlet.2013.05.643. Epub 2013 Jun 13.
• [49] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [50] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.