Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBHH882)

• DOT Name: Kelch domain-containing protein 2 (KLHDC2)
• Synonyms: Hepatocellular carcinoma-associated antigen 33; Host cell factor homolog LCP; Host cell factor-like protein 1; HCLP-1
• Gene Name: KLHDC2
• Related Disease:
  Melanoma
  Advanced cancer
  Breast neoplasm
  Dementia
  Neoplasm
  Tuberculosis
  Gingivitis
  Carcinoma of liver and intrahepatic biliary tract
  Hepatocellular carcinoma
  Liver cancer
• UniProt ID: KLDC2_HUMAN
• PDB ID: 6DO3; 6DO4; 6DO5; 8EBL; 8EBM; 8EBN; 8PIF
• Pfam ID: PF13418
• Sequence:
  MADGNEDLRADDLPGPAFESYESMELACPAERSGHVAVSDGRHMFVWGGYKSNQVRGLYD
  FYLPREELWIYNMETGRWKKINTEGDVPPSMSGSCAVCVDRVLYLFGGHHSRGNTNKFYM
  LDSRSTDRVLQWERIDCQGIPPSSKDKLGVWVYKNKLIFFGGYGYLPEDKVLGTFEFDET
  SFWNSSHPRGWNDHVHILDTETFTWSQPITTGKAPSPRAAHACATVGNRGFVFGGRYRDA
  RMNDLHYLNLDTWEWNELIPQGICPVGRSWHSLTPVSSDHLFLFGGFTTDKQPLSDAWTY
  CISKNEWIQFNHPYTEKPRLWHTACASDEGEVIVFGGCANNLLVHHRAAHSNEILIFSVQ
  PKSLVRLSLEAVICFKEMLANSWNCLPKHLLHSVNQRFGSNNTSGS
• Function: Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(KLHDC2) complex specifically recognizes proteins with a diglycine (Gly-Gly) at the C-terminus, leading to their ubiquitination and degradation. The CRL2(KLHDC2) complex mediates ubiquitination and degradation of truncated SELENOK and SELENOS selenoproteins produced by failed UGA/Sec decoding, which end with a diglycine. The CRL2(KLHDC2) complex also recognizes proteolytically cleaved proteins ending with Gly-Gly, such as the N-terminal fragment of USP1, leading to their degradation. May also act as an indirect repressor of CREB3-mediated transcription by interfering with CREB3-DNA-binding.
• Tissue Specificity: Widely expressed, with high levels in skeletal muscle, heart, pancreas and liver . Undetectable in peripheral blood leukocytes .

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Dementia	DISXL1WY	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[5]
Gingivitis	DISC8RMX	moderate	Biomarker	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[7]
Liver cancer	DISDE4BI	Limited	Biomarker	[7]

14 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 2 (KLHDC2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kelch domain-containing protein 2 (KLHDC2).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[15]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Kelch domain-containing protein 2 (KLHDC2).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Kelch domain-containing protein 2 (KLHDC2).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Kelch domain-containing protein 2 (KLHDC2).	[21]

References

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• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [16] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.