Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQT85SN)

• DOT Name: BTB/POZ domain-containing protein KCTD21 (KCTD21)
• Synonyms: KCASH2 protein; Potassium channel tetramerization domain-containing protein 21
• Gene Name: KCTD21
• Related Disease:
  Medulloblastoma
  Intellectual disability
  Schizophrenia
• UniProt ID: KCD21_HUMAN
• Pfam ID: PF02214 ; PF19329
• Sequence:
  MSDPITLNVGGKLYTTSLATLTSFPDSMLGAMFSGKMPTKRDSQGNCFIDRDGKVFRYIL
  NFLRTSHLDLPEDFQEMGLLRREADFYQVQPLIEALQEKEVELSKAEKNAMLNITLNQRV
  QTVHFTVREAPQIYSLSSSSMEVFNANIFSTSCLFLKLLGSKLFYCSNGNLSSITSHLQD
  PNHLTLDWVANVEGLPEEEYTKQNLKRLWVVPANKQINSFQVFVEEVLKIALSDGFCIDS
  SHPHALDFMNNKIIRLIRYR
• 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. 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).
• Tissue Specificity: Highly expressed in cerebellum and brain. Expression is down-regulated in medulloblastoma.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[1]
Intellectual disability	DISMBNXP	Disputed	Biomarker	[2]
Schizophrenia	DISSRV2N	Disputed	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[3]

9 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 BTB/POZ domain-containing protein KCTD21 (KCTD21).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[6]
Menadione	DMSJDTY	Approved	Menadione affects the expression of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BTB/POZ domain-containing protein KCTD21 (KCTD21).	[11]

References

• [1] KCTD15 inhibits the Hedgehog pathway in Medulloblastoma cells by increasing protein levels of the oncosuppressor KCASH2.Oncogenesis. 2019 Nov 4;8(11):64. doi: 10.1038/s41389-019-0175-6.
• [2] Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families.Sci Rep. 2017 Jul 18;7(1):5679. doi: 10.1038/s41598-017-06033-1.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [7] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [10] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [11] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.