Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNS9A29)

• DOT Name: Homeobox protein aristaless-like 4 (ALX4)
• Gene Name: ALX4
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Frontonasal dysplasia with alopecia and genital anomaly
  Parietal foramina 2
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Craniofrontonasal syndrome
  Frontonasal dysplasia
  Liver cancer
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Major depressive disorder
  Medulloblastoma
  Neoplasm
  Non-insulin dependent diabetes
  Polydactyly
  Polyp
  Refractory multiple myeloma
  Syndactyly
  Adenocarcinoma
  Adult hepatocellular carcinoma
  Advanced cancer
  Cholangiocarcinoma
  Colon cancer
  Colon carcinoma
  Colorectal adenoma
  Craniosynostosis
  Parietal foramina
  Acute myelogenous leukaemia
  Adams-Oliver syndrome 1
  Gout
  Potocki-Shaffer syndrome
• UniProt ID: ALX4_HUMAN
• PDB ID: 2M0C
• Pfam ID: PF00046 ; PF03826
• Sequence:
  MNAETCVSYCESPAAAMDAYYSPVSQSREGSSPFRAFPGGDKFGTTFLSAAAKAQGFGDA
  KSRARYGAGQQDLATPLESGAGARGSFNKFQPQPSTPQPQPPPQPQPQQQQPQPQPPAQP
  HLYLQRGACKTPPDGSLKLQEGSSGHSAALQVPCYAKESSLGEPELPPDSDTVGMDSSYL
  SVKEAGVKGPQDRASSDLPSPLEKADSESNKGKKRRNRTTFTSYQLEELEKVFQKTHYPD
  VYAREQLAMRTDLTEARVQVWFQNRRAKWRKRERFGQMQQVRTHFSTAYELPLLTRAENY
  AQIQNPSWLGNNGAASPVPACVVPCDPVPACMSPHAHPPGSGASSVTDFLSVSGAGSHVG
  QTHMGSLFGAASLSPGLNGYELNGEPDRKTSSIAALRMKAKEHSAAISWAT
• Function: Transcription factor involved in skull and limb development. Plays an essential role in craniofacial development, skin and hair follicle development.
• Tissue Specificity: Expression is likely to be restricted to bone. Found in parietal bone.

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Frontonasal dysplasia with alopecia and genital anomaly	DISRYHZA	Definitive	Autosomal recessive	[2]
Parietal foramina 2	DISOPIWR	Definitive	Autosomal dominant	[2]
Thyroid cancer	DIS3VLDH	Definitive	Altered Expression	[3]
Thyroid gland carcinoma	DISMNGZ0	Definitive	Altered Expression	[3]
Thyroid tumor	DISLVKMD	Definitive	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[4]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Craniofrontonasal syndrome	DISSO9WK	Strong	Biomarker	[6]
Frontonasal dysplasia	DISXV4YX	Strong	Genetic Variation	[7]
Liver cancer	DISDE4BI	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Lung neoplasm	DISVARNB	Strong	Biomarker	[8]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[9]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[12]
Polydactyly	DIS25BMZ	Strong	Biomarker	[13]
Polyp	DISRSLYF	Strong	Biomarker	[14]
Refractory multiple myeloma	DIS606GH	Strong	Genetic Variation	[15]
Syndactyly	DISZK2BT	Strong	Biomarker	[16]
Adenocarcinoma	DIS3IHTY	moderate	Posttranslational Modification	[17]
Adult hepatocellular carcinoma	DIS6ZPAI	moderate	Biomarker	[17]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[17]
Cholangiocarcinoma	DIS71F6X	moderate	Biomarker	[17]
Colon cancer	DISVC52G	moderate	Posttranslational Modification	[17]
Colon carcinoma	DISJYKUO	moderate	Posttranslational Modification	[17]
Colorectal adenoma	DISTSVHM	moderate	Posttranslational Modification	[17]
Craniosynostosis	DIS6J405	moderate	Biomarker	[6]
Parietal foramina	DISS1N5X	Supportive	Autosomal dominant	[18]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[19]
Adams-Oliver syndrome 1	DISC3I62	Limited	Genetic Variation	[20]
Gout	DISHC0U7	Limited	Genetic Variation	[21]
Potocki-Shaffer syndrome	DISKGU59	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Homeobox protein aristaless-like 4 (ALX4).	[22]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein aristaless-like 4 (ALX4).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Homeobox protein aristaless-like 4 (ALX4).	[27]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine decreases the methylation of Homeobox protein aristaless-like 4 (ALX4).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein aristaless-like 4 (ALX4).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein aristaless-like 4 (ALX4).	[26]

References

• [1] Epigenetic silencing of ALX4 regulates microcystin-LR induced hepatocellular carcinoma through the P53 pathway.Sci Total Environ. 2019 Sep 15;683:317-330. doi: 10.1016/j.scitotenv.2019.05.144. Epub 2019 May 15.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Downregulated long noncoding RNA LINC00313 inhibits the epithelial-mesenchymal transition, invasion, and migration of thyroid cancer cells through inhibiting the methylation of ALX4.J Cell Physiol. 2019 Nov;234(11):20992-21004. doi: 10.1002/jcp.28703. Epub 2019 May 15.
• [4] ALX4, an epigenetically down regulated tumor suppressor, inhibits breast cancer progression by interfering Wnt/-catenin pathway.J Exp Clin Cancer Res. 2017 Nov 28;36(1):170. doi: 10.1186/s13046-017-0643-9.
• [5] Development of a multiplex MethyLight assay for the detection of multigene methylation in human colorectal cancer.Cancer Genet Cytogenet. 2010 Oct 1;202(1):1-10. doi: 10.1016/j.cancergencyto.2010.05.018.
• [6] Potocki-Shaffer deletion encompassing ALX4 in a patient with frontonasal dysplasia phenotype.Am J Med Genet A. 2014 Feb;164A(2):346-52. doi: 10.1002/ajmg.a.36140. Epub 2013 Dec 13.
• [7] Identification of a novel homozygous ALX4 mutation in two unrelated patients with frontonasal dysplasia type-2.Am J Med Genet A. 2018 May;176(5):1190-1194. doi: 10.1002/ajmg.a.38655.
• [8] Epigenetic silencing of Aristaless-like homeobox-4, a potential tumor suppressor gene associated with lung cancer. Int J Cancer. 2014 Mar 15;134(6):1311-22. doi: 10.1002/ijc.28472. Epub 2013 Nov 11.
• [9] Association of Novel ALX4 Gene Polymorphisms with Antidepressant Treatment Response: Findings from the CO-MED Trial.Mol Neuropsychiatry. 2018 Jun;4(1):7-19. doi: 10.1159/000487321. Epub 2018 May 3.
• [10] Identification of FoxR2 as an oncogene in medulloblastoma.Cancer Res. 2014 Apr 15;74(8):2351-61. doi: 10.1158/0008-5472.CAN-13-1523. Epub 2014 Mar 5.
• [11] Overexpression of Aristaless-Like Homeobox-4 Inhibits Proliferation, Invasion, and EMT in Hepatocellular Carcinoma Cells.Oncol Res. 2017 Jan 2;25(1):11-18. doi: 10.3727/096504016X14685034103833.
• [12] A Perception on Genome-Wide Genetic Analysis of Metabolic Traits in Arab Populations.Front Endocrinol (Lausanne). 2019 Jan 28;10:8. doi: 10.3389/fendo.2019.00008. eCollection 2019.
• [13] Physical and genetic interactions between Alx4 and Cart1.Development. 1999 Jan;126(2):359-69. doi: 10.1242/dev.126.2.359.
• [14] Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions.PLoS One. 2010 Feb 4;5(2):e9061. doi: 10.1371/journal.pone.0009061.
• [15] A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies.Am J Med Genet A. 2015 Dec;167A(12):3011-8. doi: 10.1002/ajmg.a.37344. Epub 2015 Sep 3.
• [16] The bovine aristaless-like homeobox 4 (ALX4) as a candidate gene for syndactyly.Cytogenet Genome Res. 2006;115(2):123-8. doi: 10.1159/000095231.
• [17] Aristaless-like homeobox-4 gene methylation is a potential marker for colorectal adenocarcinomas.Gastroenterology. 2006 Nov;131(5):1418-30. doi: 10.1053/j.gastro.2006.08.034. Epub 2006 Aug 18.
• [18] Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype. Eur J Hum Genet. 2006 Feb;14(2):151-8. doi: 10.1038/sj.ejhg.5201526.
• [19] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [20] Clinical and molecular analysis of nine families with Adams-Oliver syndrome.Eur J Hum Genet. 2003 Jun;11(6):457-63. doi: 10.1038/sj.ejhg.5200980.
• [21] Gout and type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences.Rheumatology (Oxford). 2012 Apr;51(4):715-20. doi: 10.1093/rheumatology/ker373. Epub 2011 Dec 16.
• [22] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] Epigenetic silencing of Aristaless-like homeobox-4, a potential tumor suppressor gene associated with lung cancer. Int J Cancer. 2014 Mar 15;134(6):1311-22. doi: 10.1002/ijc.28472. Epub 2013 Nov 11.
• [25] 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.
• [26] 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.
• [27] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.