Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKP6LCR)

• DOT Name: Kelch domain-containing protein 8B (KLHDC8B)
• Gene Name: KLHDC8B
• Related Disease:
  Adult lymphoma
  Advanced cancer
  Alzheimer disease
  B-cell lymphoma
  Cognitive impairment
  Lymphoma
  Lymphoproliferative syndrome
  Major depressive disorder
  Mood disorder
  Neoplasm
  Pediatric lymphoma
  Kidney cancer
  Renal carcinoma
  Sensorineural hearing loss disorder
  Classic Hodgkin lymphoma
  Epstein barr virus infection
  Membranous glomerulonephritis
• UniProt ID: KLD8B_HUMAN
• Pfam ID: PF01344
• Sequence:
  MSAGGGRAFAWQVFPPMPTCRVYGTVAHQDGHLLVLGGCGRAGLPLDTAETLDMASHTWL
  ALAPLPTARAGAAAVVLGKQVLVVGGVDEVQSPVAAVEAFLMDEGRWERRATLPQAAMGV
  ATVERDGMVYALGGMGPDTAPQAQVRVYEPRRDCWLSLPSMPTPCYGASTFLHGNKIYVL
  GGRQGKLPVTAFEAFDLEARTWTRHPSLPSRRAFAGCAMAEGSVFSLGGLQQPGPHNFYS
  RPHFVNTVEMFDLEHGSWTKLPRSLRMRDKRADFVVGSLGGHIVAIGGLGNQPCPLGSVE
  SFSLARRRWEALPAMPTARCSCSSLQAGPRLFVIGGVAQGPSQAVEALCLRDGV
• Function: Involved in pinching off the separated nuclei at the cleavage furrow and in cytokinesis. Required for mitotic integrity and maintenance of chromosomal stability. Protects cells against mitotic errors, centrosomal amplification, micronucleus formation and aneuploidy. Plays a key role of midbody function involving abscission of the daughter cells during cytokinesis and appropriate chromosomal and nuclear segregation into the daughter cells.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[3]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[2]
Lymphoma	DISN6V4S	Strong	Biomarker	[1]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[3]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[1]
Kidney cancer	DISBIPKM	moderate	Biomarker	[6]
Renal carcinoma	DISER9XT	moderate	Biomarker	[6]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Genetic Variation	[7]
Classic Hodgkin lymphoma	DISV1LU6	Limited	Unknown	[1]
Epstein barr virus infection	DISOO0WT	Limited	Biomarker	[8]
Membranous glomerulonephritis	DISFSUKQ	Limited	Biomarker	[9]

9 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 Kelch domain-containing protein 8B (KLHDC8B).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kelch domain-containing protein 8B (KLHDC8B).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Kelch domain-containing protein 8B (KLHDC8B).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Kelch domain-containing protein 8B (KLHDC8B).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kelch domain-containing protein 8B (KLHDC8B).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kelch domain-containing protein 8B (KLHDC8B).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Kelch domain-containing protein 8B (KLHDC8B).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Kelch domain-containing protein 8B (KLHDC8B).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kelch domain-containing protein 8B (KLHDC8B).	[19]

2 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 decreases the methylation of Kelch domain-containing protein 8B (KLHDC8B).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Kelch domain-containing protein 8B (KLHDC8B).	[18]

References

• [1] Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14920-5. doi: 10.1073/pnas.0904231106. Epub 2009 Aug 12.
• [2] Nicotine versus 6-hydroxy-l-nicotine against chlorisondamine induced memory impairment and oxidative stress in the rat hippocampus.Biomed Pharmacother. 2017 Feb;86:102-108. doi: 10.1016/j.biopha.2016.12.008. Epub 2016 Dec 9.
• [3] Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: Comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types.Cancer Sci. 2017 Jun;108(6):1271-1280. doi: 10.1111/cas.13249. Epub 2017 May 23.
• [4] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [5] Immunohistochemical assessment of the diagnostic utility of PD-L1: a preliminary analysis of anti-PD-L1 antibody (SP142) for lymphoproliferative diseases with tumour and non-malignant Hodgkin-Reed-Sternberg (HRS)-like cells.Histopathology. 2018 Jun;72(7):1156-1163. doi: 10.1111/his.13475. Epub 2018 Mar 9.
• [6] De novo design of thioredoxin reductase-targeted heterometallic titanocene-gold compounds of chlorambucil for mechanistic insights into renal cancer.Chem Commun (Camb). 2019 Dec 19;56(2):297-300. doi: 10.1039/c9cc07406f.
• [7] Visual speech alters the discrimination and identification of non-intact auditory speech in children with hearing loss.Int J Pediatr Otorhinolaryngol. 2017 Mar;94:127-137. doi: 10.1016/j.ijporl.2017.01.009. Epub 2017 Jan 9.
• [8] Epidemiology and outcome of chronic high Epstein-Barr viral load carriage in pediatric kidney transplant recipients.Pediatr Transplant. 2018 May;22(3):e13147. doi: 10.1111/petr.13147. Epub 2018 Feb 6.
• [9] Chlormethine Hydrochloride is Not Inferior to Tacrolimus in Treating Steroid-Resistant Nephrotic Syndrome.Kidney Blood Press Res. 2018;43(1):68-79. doi: 10.1159/000486911. Epub 2018 Jan 24.
• [10] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [11] 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.
• [12] 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.
• [13] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] 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.
• [18] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [19] 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.