Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE3MWYJ)

• DOT Name: Forkhead box protein N4 (FOXN4)
• Gene Name: FOXN4
• Related Disease:
  Breast cancer
  Breast carcinoma
  Neoplasm
• UniProt ID: FOXN4_HUMAN
• Pfam ID: PF00250
• Sequence:
  MIESDTSSIMSGIIRNSGQNHHPSPQEYRLLATTSDDDLPGDLQSLSWLTAVDVPRLQQM
  ASGRVDLGGPCVPHPHPGALAGVADLHVGATPSPLLHGPAGMAPRGMPGLGPITGHRDSM
  SQFPVGGQPSSGLQDPPHLYSPATQPQFPLPPGAQQCPPVGLYGPPFGVRPPYPQPHVAV
  HSSQELHPKHYPKPIYSYSCLIAMALKNSKTGSLPVSEIYSFMKEHFPYFKTAPDGWKNS
  VRHNLSLNKCFEKVENKMSGSSRKGCLWALNLARIDKMEEEMHKWKRKDLAAIHRSMANP
  EELDKLISDRPESCRRPGKPGEPEAPVLTHATTVAVAHGCLAVSQLPPQPLMTLSLQSVP
  LHHQVQPQAHLAPDSPAPAQTPPLHALPDLSPSPLPHPAMGRAPVDFINISTDMNTEVDA
  LDPSIMDFALQGNLWEEMKDEGFSLDTLGAFADSPLGCDLGASGLTPASGGSDQSFPDLQ
  VTGLYTAYSTPDSVAASGTSSSSQYLGAQGNKPIALL
• Function: Transcription factor essential for neural and some non-neural tissues development, such as retina and lung respectively. Binds to an 11-bp consensus sequence containing the invariant tetranucleotide 5'-ACGC-3'. During development of the central nervous system, is required to specify the amacrine and horizontal cell fates from multipotent retinal progenitors while suppressing the alternative photoreceptor cell fates through activating DLL4-NOTCH signaling. Also acts synergistically with ASCL1/MASH1 to activate DLL4-NOTCH signaling and drive commitment of p2 progenitors to the V2b interneuron fates during spinal cord neurogenesis. In development of non-neural tissues, plays an essential role in the specification of the atrioventricular canal and is indirectly required for patterning the distal airway during lung development.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Limited	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[1]
Neoplasm	DISZKGEW	Limited	Biomarker	[1]

3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Forkhead box protein N4 (FOXN4).	[2]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Forkhead box protein N4 (FOXN4).	[3]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Forkhead box protein N4 (FOXN4).	[5]

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 Forkhead box protein N4 (FOXN4).	[4]

References

• [1] Identification of FOXN4 as a tumor suppressor of breast carcinogenesis via the activation of TP53 and deactivation of Notch signaling.Gene. 2020 Jan 5;722:144057. doi: 10.1016/j.gene.2019.144057. Epub 2019 Aug 17.
• [2] 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.
• [3] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [4] 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.
• [5] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.