Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6VYX67)

• DOT Name: F-box only protein 4 (FBXO4)
• Gene Name: FBXO4
• Related Disease:
  Esophageal squamous cell carcinoma
  Neoplasm
  Head-neck squamous cell carcinoma
  Metastatic malignant neoplasm
  Advanced cancer
  Lung cancer
  Lung carcinoma
• UniProt ID: FBX4_HUMAN
• PDB ID: 3L2O; 3L82
• Pfam ID: PF12937
• Sequence:
  MAGSEPRSGTNSPPPPFSDWGRLEAAILSGWKTFWQSVSKERVARTTSREEVDEAASTLT
  RLPIDVQLYILSFLSPHDLCQLGSTNHYWNETVRDPILWRYFLLRDLPSWSSVDWKSLPD
  LEILKKPISEVTDGAFFDYMAVYRMCCPYTRRASKSSRPMYGAVTSFLHSLIIQNEPRFA
  MFGPGLEELNTSLVLSLMSSEELCPTAGLPQRQIDGIGSGVNFQLNNQHKFNILILYSTT
  RKERDRAREEHTSAVNKMFSRHNEGDDQQGSRYSVIPQIQKVCEVVDGFIYVANAEAHKR
  HEWQDEFSHIMAMTDPAFGSSGRPLLVLSCISQGDVKRMPCFYLAHELHLNLLNHPWLVQ
  DTEAETLTGFLNGIEWILEEVESKRAR
• Function: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Promotes ubiquitination of CCND1 and its subsequent proteasomal degradation. Recognizes TERF1 and promotes its ubiquitination together with UBE2D1. Promotes ubiquitination of FXR1 following phosphorylation of FXR1 by GSK3B, leading to FXR1 degradation by the proteasome.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Antigen processing (R-HSA-983168)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[4]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[1]
Lung cancer	DISCM4YA	Limited	Biomarker	[5]
Lung carcinoma	DISTR26C	Limited	Biomarker	[5]

10 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 F-box only protein 4 (FBXO4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of F-box only protein 4 (FBXO4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of F-box only protein 4 (FBXO4).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of F-box only protein 4 (FBXO4).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of F-box only protein 4 (FBXO4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of F-box only protein 4 (FBXO4).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of F-box only protein 4 (FBXO4).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of F-box only protein 4 (FBXO4).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-box only protein 4 (FBXO4).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of F-box only protein 4 (FBXO4).	[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 increases the methylation of F-box only protein 4 (FBXO4).	[11]

References

• [1] Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma.Nat Commun. 2019 Mar 21;10(1):1296. doi: 10.1038/s41467-019-09179-w.
• [2] The RNA-binding protein FXR1 modulates prostate cancer progression by regulating FBXO4.Funct Integr Genomics. 2019 May;19(3):487-496. doi: 10.1007/s10142-019-00661-8. Epub 2019 Feb 11.
• [3] Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma.Nat Commun. 2017 Nov 16;8(1):1534. doi: 10.1038/s41467-017-01199-8.
• [4] Regulation of FBXO4-mediated ICAM-1 protein stability in metastatic breast cancer.Oncotarget. 2017 Sep 15;8(47):83100-83113. doi: 10.18632/oncotarget.20912. eCollection 2017 Oct 10.
• [5] FBXO4 inhibits lung cancer cell survival by targeting Mcl-1 for degradation.Cancer Gene Ther. 2017 Aug;24(8):342-347. doi: 10.1038/cgt.2017.24. Epub 2017 Aug 4.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.