Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC22GE4)

• DOT Name: BTB/POZ domain-containing protein KCTD6 (KCTD6)
• Synonyms: KCASH3 protein; Potassium channel tetramerization domain-containing protein 6
• Gene Name: KCTD6
• Related Disease: Medulloblastoma
• UniProt ID: KCTD6_HUMAN
• Pfam ID: PF02214
• Sequence:
  MDNGDWGYMMTDPVTLNVGGHLYTTSLTTLTRYPDSMLGAMFGGDFPTARDPQGNYFIDR
  DGPLFRYVLNFLRTSELTLPLDFKEFDLLRKEADFYQIEPLIQCLNDPKPLYPMDTFEEV
  VELSSTRKLSKYSNPVAVIITQLTITTKVHSLLEGISNYFTKWNKHMMDTRDCQVSFTFG
  PCDYHQEVSLRVHLMEYITKQGFTIRNTRVHHMSERANENTVEHNWTFCRLARKTDD
• Function: Probable substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex mediating the ubiquitination and subsequent proteasomal degradation of target proteins. Promotes the ubiquitination of HDAC1; the function seems to depend on KCTD11:KCTD6 oligomerization. Can function as antagonist of the Hedgehog pathway by affecting the nuclear transfer of transcription factor GLI1; the function probably occurs via HDAC1 down-regulation, keeping GLI1 acetylated and inactive. Inhibits cell growth and tumorigenicity of medulloblastoma (MDB). Involved in regulating protein levels of ANK1 isoform Mu17 probably implicating CUL3-dependent proteasomal degradation.
• Tissue Specificity: Highly expressed in cerebellum and brain. Expression is down-regulated in medulloblastoma.
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Antigen processing (R-HSA-983168)
  RUNX1 regulates estrogen receptor mediated transcription (R-HSA-8931987)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[1]

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 BTB/POZ domain-containing protein KCTD6 (KCTD6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of BTB/POZ domain-containing protein KCTD6 (KCTD6).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BTB/POZ domain-containing protein KCTD6 (KCTD6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BTB/POZ domain-containing protein KCTD6 (KCTD6).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of BTB/POZ domain-containing protein KCTD6 (KCTD6).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of BTB/POZ domain-containing protein KCTD6 (KCTD6).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of BTB/POZ domain-containing protein KCTD6 (KCTD6).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BTB/POZ domain-containing protein KCTD6 (KCTD6).	[11]

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 BTB/POZ domain-containing protein KCTD6 (KCTD6).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of BTB/POZ domain-containing protein KCTD6 (KCTD6).	[10]

References

• [1] Identification and characterization of KCASH2 and KCASH3, 2 novel Cullin3 adaptors suppressing histone deacetylase and Hedgehog activity in medulloblastoma.Neoplasia. 2011 Apr;13(4):374-85. doi: 10.1593/neo.101630.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.