Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase KCMF1 (KCMF1)
• Synonyms: EC 2.3.2.27; FGF-induced in gastric cancer; Potassium channel modulatory factor; PCMF; RING-type E3 ubiquitin transferase KCMF1; ZZ-type zinc finger-containing protein 1
• Gene Name: KCMF1
• Related Disease:
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  Neoplasm
  Pancreatic cancer
  Sarcoma
  Gastric neoplasm
  Intellectual disability
• UniProt ID: KCMF1_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF05605 ; PF00569
• Sequence:
  MSRHEGVSCDACLKGNFRGRRYKCLICYDYDLCASCYESGATTTRHTTDHPMQCILTRVD
  FDLYYGGEAFSVEQPQSFTCPYCGKMGYTETSLQEHVTSEHAETSTEVICPICAALPGGD
  PNHVTDDFAAHLTLEHRAPRDLDESSGVRHVRRMFHPGRGLGGPRARRSNMHFTSSSTGG
  LSSSQSSYSPSNREAMDPIAELLSQLSGVRRSAGGQLNSSGPSASQLQQLQMQLQLERQH
  AQAARQQLETARNATRRTNTSSVTTTITQSTATTNIANTESSQQTLQNSQFLLTRLNDPK
  MSETERQSMESERADRSLFVQELLLSTLVREESSSSDEDDRGEMADFGAMGCVDIMPLDV
  ALENLNLKESNKGNEPPPPPL
• Function: Has intrinsic E3 ubiquitin ligase activity and promotes ubiquitination.
• Tissue Specificity: Spleen, small intestine, ovary, peripheral blood, lung, kidney and pancreas. Expressed at low levels in the thymus, prostate, testis, colon, heart, brain, placenta and liver.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Pancreatic cancer	DISJC981	Strong	Biomarker	[1]
Sarcoma	DISZDG3U	Strong	Altered Expression	[3]
Gastric neoplasm	DISOKN4Y	Disputed	Altered Expression	[4]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	E3 ubiquitin-protein ligase KCMF1 (KCMF1) affects the response to substance of Methotrexate.	[22]

2 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 E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[18]

15 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 E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase KCMF1 (KCMF1).	[21]

References

• [1] The zinc-finger protein KCMF1 is overexpressed during pancreatic cancer development and downregulation of KCMF1 inhibits pancreatic cancer development in mice.Oncogene. 2010 Jul 15;29(28):4058-67. doi: 10.1038/onc.2010.156. Epub 2010 May 17.
• [2] Interaction of 14-3-3 with KCMF1 suppresses the proliferation and colony formation of human colon cancer stem cells.World J Gastroenterol. 2013 Jun 28;19(24):3770-80. doi: 10.3748/wjg.v19.i24.3770.
• [3] Suppression of KCMF1 by constitutive high CD99 expression is involved in the migratory ability of Ewing's sarcoma cells.Oncogene. 2006 May 4;25(19):2795-800. doi: 10.1038/sj.onc.1209300.
• [4] FIGC, a novel FGF-induced ubiquitin-protein ligase in gastric cancers.FEBS Lett. 2004 Dec 3;578(1-2):21-5. doi: 10.1016/j.febslet.2004.10.071.
• [5] KCMF1 (potassium channel modulatory factor 1) Links RAD6 to UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4) and lysosome-mediated degradation.Mol Cell Proteomics. 2015 Mar;14(3):674-85. doi: 10.1074/mcp.M114.042168. Epub 2015 Jan 12.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.