Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5QC0BF)

• DOT Name: Homeobox protein Nkx-6.1 (NKX6-1)
• Synonyms: Homeobox protein NK-6 homolog A
• Gene Name: NKX6-1
• Related Disease:
  Maturity-onset diabetes of the young
  Cervical cancer
  Cervical carcinoma
  Childhood kidney Wilms tumor
  Wilms tumor
  Non-insulin dependent diabetes
• UniProt ID: NKX61_HUMAN
• Pfam ID: PF00046
• Sequence:
  MLAVGAMEGTRQSAFLLSSPPLAALHSMAEMKTPLYPAAYPPLPAGPPSSSSSSSSSSSP
  SPPLGTHNPGGLKPPATGGLSSLGSPPQQLSAATPHGINDILSRPSMPVASGAALPSASP
  SGSSSSSSSSASASSASAAAAAAAAAAAAASSPAGLLAGLPRFSSLSPPPPPPGLYFSPS
  AAAVAAVGRYPKPLAELPGRTPIFWPGVMQSPPWRDARLACTPHQGSILLDKDGKRKHTR
  PTFSGQQIFALEKTFEQTKYLAGPERARLAYSLGMTESQVKVWFQNRRTKWRKKHAAEMA
  TAKKKQDSETERLKGASENEEEDDDYNKPLDPNSDDEKITQLLKKHKSSSGGGGGLLLHA
  SEPESSS
• Function: Transcription factor which binds to specific A/T-rich DNA sequences in the promoter regions of a number of genes. Involved in the development of insulin-producing beta cells in the islets of Langerhans at the secondary transition. Together with NKX2-2 and IRX3 acts to restrict the generation of motor neurons to the appropriate region of the neural tube. Belongs to the class II proteins of neuronal progenitor factors, which are induced by SHH signals.
• Tissue Specificity: Pancreatic beta cells.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  Regulation of gene expression in early pancreatic precursor cells (R-HSA-210747)
  Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Maturity-onset diabetes of the young	DISG75M5	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Disputed	Biomarker	[2]
Cervical carcinoma	DIST4S00	Disputed	Biomarker	[2]
Childhood kidney Wilms tumor	DIS0NMK3	Disputed	Genetic Variation	[2]
Wilms tumor	DISB6T16	Disputed	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[3]

3 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 Homeobox protein Nkx-6.1 (NKX6-1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein Nkx-6.1 (NKX6-1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Homeobox protein Nkx-6.1 (NKX6-1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homeobox protein Nkx-6.1 (NKX6-1).	[5]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Homeobox protein Nkx-6.1 (NKX6-1).	[8]

References

• [1] Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India.BMC Med Genet. 2018 Feb 13;19(1):22. doi: 10.1186/s12881-018-0528-6.
• [2] Methylation in the promoter regions of WT1, NKX6-1 and DBC1 genes in cervical cancer tissues of Uygur women in Xinjiang.Genet Mol Biol. 2018 Jan-Mar;41(1):9-17. doi: 10.1590/1678-4685-GMB-2016-0146.
• [3] Chronic hyperglycemia, independent of plasma lipid levels, is sufficient for the loss of beta-cell differentiation and secretory function in the db/db mouse model of diabetes.Diabetes. 2005 Sep;54(9):2755-63. doi: 10.2337/diabetes.54.9.2755.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [8] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.