Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT64DFBU)

• DOT Name: BTB/POZ domain-containing protein KCTD11 (KCTD11)
• Synonyms: KCASH1 protein; Potassium channel tetramerization domain-containing protein 11; RING-type E3 ubiquitin transferase subunit KCTD11
• Gene Name: KCTD11
• Related Disease:
  Hepatocellular carcinoma
  Hereditary hemochromatosis
  Lung cancer
  Lung carcinoma
  Neoplasm
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: KCD11_HUMAN
• Pfam ID: PF02214 ; PF19329
• Sequence:
  MLGAMFRAGTPMPPNLNSQGGGHYFIDRDGKAFRHILNFLRLGRLDLPRGYGETALLRAE
  ADFYQIRPLLDALRELEASQGTPAPTAALLHADVDVSPRLVHFSARRGPHHYELSSVQVD
  TFRANLFCTDSECLGALRARFGVASGDRAEGSPHFHLEWAPRPVELPEVEYGRLGLQPLW
  TGGPGERREVVGTPSFLEEVLRVALEHGFRLDSVFPDPEDLLNSRSLRFVRH
• Function: Plays a role as a marker and a regulator of neuronal differentiation; Up-regulated by a variety of neurogenic signals, such as retinoic acid, epidermal growth factor/EGF and NGFB/nerve growth factor. Induces apoptosis, growth arrest and the expression of cyclin-dependent kinase inhibitor CDKN1B. Plays a role as a tumor repressor and inhibits cell growth and tumorigenicity of medulloblastoma (MDB). Acts as a probable substrate-specific adapter for a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex towards HDAC1. Functions as antagonist of the Hedgehog pathway on cell proliferation and differentiation by affecting the nuclear transfer of transcription factor GLI1, thus maintaining cerebellar granule cells in undifferentiated state, this effect probably occurs via HDAC1 down-regulation, keeping GLI1 acetylated and inactive. When knock-down, Hedgehog antagonism is impaired and proliferation of granule cells is sustained. Activates the caspase cascade.
• Tissue Specificity: Higher expression in cerebellum than in whole brain and lower expression in medulloblastoma.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Prostate adenocarcinoma	DISBZYU8	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]

10 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 BTB/POZ domain-containing protein KCTD11 (KCTD11).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BTB/POZ domain-containing protein KCTD11 (KCTD11).	[15]

1 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 BTB/POZ domain-containing protein KCTD11 (KCTD11).	[12]

References

• [1] KCTD11 inhibits growth and metastasis of hepatocellular carcinoma through activating Hippo signaling.Oncotarget. 2017 Jun 6;8(23):37717-37729. doi: 10.18632/oncotarget.17145.
• [2] KCTD11 tumor suppressor gene expression is reduced in prostate adenocarcinoma.Biomed Res Int. 2014;2014:380398. doi: 10.1155/2014/380398. Epub 2014 Jun 19.
• [3] Copy number variations of chromosome 17p13.1 might be linked to high risk of lung cancer in heavy smokers.Mol Biol Rep. 2011 Nov;38(8):5211-7. doi: 10.1007/s11033-010-0672-3. Epub 2011 Jan 4.
• [4] Induction of tumor suppressor KCTD11 during periovulatory period in rat ovary.Reprod Biol. 2019 Jun;19(2):173-178. doi: 10.1016/j.repbio.2019.05.003. Epub 2019 May 28.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.