Details of Drug Off-Target (DOT)

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

• DOT Name: Paired box protein Pax-7 (PAX7)
• Synonyms: HuP1
• Gene Name: PAX7
• Related Disease:
  Oculopharyngeal muscular dystrophy
  Adult glioblastoma
  Advanced cancer
  Breast neoplasm
  Carcinoma
  Cleft lip/palate
  Cushing disease
  Desmoplastic small round cell tumor
  Duchenne muscular dystrophy
  facioscapulohumeral muscular dystrophy
  Glioblastoma multiforme
  Isolated cleft lip
  Lung squamous cell carcinoma
  Lymphoproliferative syndrome
  Malignant soft tissue neoplasm
  Myopathy
  Myopathy, congenital, progressive, with scoliosis
  Neuromuscular disease
  Ptosis
  Sarcoma
  Soft tissue neoplasm
  Spinal muscular atrophy
  Synovial sarcoma
  Zika virus infection
  Congenital myopathy with myasthenic-like onset
  Ewing sarcoma
  Fetal growth restriction
  Neurofibromatosis type 1
  Osteoarthritis
  Rhabdomyosarcoma
  Bone osteosarcoma
  Cutaneous melanoma
  Myasthenia gravis
  Osteosarcoma
• UniProt ID: PAX7_HUMAN
• Pfam ID: PF00046 ; PF00292 ; PF12360
• Sequence:
  MAALPGTVPRMMRPAPGQNYPRTGFPLEVSTPLGQGRVNQLGGVFINGRPLPNHIRHKIV
  EMAHHGIRPCVISRQLRVSHGCVSKILCRYQETGSIRPGAIGGSKPRQVATPDVEKKIEE
  YKRENPGMFSWEIRDRLLKDGHCDRSTVPSGLVSSISRVLRIKFGKKEEEDEADKKEDDG
  EKKAKHSIDGILGDKGNRLDEGSDVESEPDLPLKRKQRRSRTTFTAEQLEELEKAFERTH
  YPDIYTREELAQRTKLTEARVQVWFSNRRARWRKQAGANQLAAFNHLLPGGFPPTGMPTL
  PPYQLPDSTYPTTTISQDGGSTVHRPQPLPPSTMHQGGLAAAAAAADTSSAYGARHSFSS
  YSDSFMNPAAPSNHMNPVSNGLSPQVMSILGNPSAVPPQPQADFSISPLHGGLDSATSIS
  ASCSQRADSIKPGDSLPTSQAYCPPTYSTTGYSVDPVAGYQYGQYGQTAVDYLAKNVSLS
  TQRRMKLGEHSAVLGLLPVETGQAY
• Function: Transcription factor that is involved in the regulation of muscle stem cells proliferation, playing a role in myogenesis and muscle regeneration.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Oculopharyngeal muscular dystrophy	DISF4G07	Definitive	Altered Expression	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[5]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[6]
Cushing disease	DISOG6P2	Strong	Altered Expression	[7]
Desmoplastic small round cell tumor	DISLI2ME	Strong	Altered Expression	[3]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Altered Expression	[8]
facioscapulohumeral muscular dystrophy	DISSE0H0	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[10]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[5]
Lymphoproliferative syndrome	DISMVL8O	Strong	Posttranslational Modification	[11]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[12]
Myopathy	DISOWG27	Strong	Altered Expression	[13]
Myopathy, congenital, progressive, with scoliosis	DIS367X6	Strong	Autosomal recessive	[13]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[14]
Ptosis	DISJZNIY	Strong	Biomarker	[13]
Sarcoma	DISZDG3U	Strong	Biomarker	[12]
Soft tissue neoplasm	DISP2OHE	Strong	Genetic Variation	[15]
Spinal muscular atrophy	DISTLKOB	Strong	Altered Expression	[16]
Synovial sarcoma	DISEZJS7	Strong	Altered Expression	[3]
Zika virus infection	DISQUCTY	Strong	Biomarker	[17]
Congenital myopathy with myasthenic-like onset	DIS73Q1D	Moderate	Autosomal recessive	[18]
Ewing sarcoma	DISQYLV3	moderate	Altered Expression	[3]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[19]
Neurofibromatosis type 1	DIS53JH9	moderate	Genetic Variation	[20]
Osteoarthritis	DIS05URM	moderate	Biomarker	[21]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[22]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[23]
Cutaneous melanoma	DIS3MMH9	Limited	Altered Expression	[24]
Myasthenia gravis	DISELRCI	Limited	Biomarker	[25]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Paired box protein Pax-7 (PAX7).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Paired box protein Pax-7 (PAX7).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Paired box protein Pax-7 (PAX7).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Paired box protein Pax-7 (PAX7).	[29]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Paired box protein Pax-7 (PAX7).	[30]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Paired box protein Pax-7 (PAX7).	[31]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Paired box protein Pax-7 (PAX7).	[30]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Paired box protein Pax-7 (PAX7).	[32]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Paired box protein Pax-7 (PAX7).	[33]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Paired box protein Pax-7 (PAX7).	[30]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Paired box protein Pax-7 (PAX7).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Paired box protein Pax-7 (PAX7).	[36]
4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol	DMTMLXU	Investigative	4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol decreases the expression of Paired box protein Pax-7 (PAX7).	[29]

2 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 Paired box protein Pax-7 (PAX7).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Paired box protein Pax-7 (PAX7).	[35]

References

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• [2] PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype.Nat Commun. 2015 Dec 3;6:10068. doi: 10.1038/ncomms10068.
• [3] PAX7 immunohistochemical evaluation of Ewing sarcoma and other small round cell tumours.Histopathology. 2018 Oct;73(4):645-652. doi: 10.1111/his.13689. Epub 2018 Aug 2.
• [4] Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer.Mol Cancer Ther. 2017 Dec;16(12):2747-2758. doi: 10.1158/1535-7163.MCT-17-0717. Epub 2017 Oct 4.
• [5] Gene amplification at chromosome 1pter-p33 including the genes PAX7 and ENO1 in squamous cell lung carcinoma.Int J Oncol. 2000 Jul;17(1):67-73. doi: 10.3892/ijo.17.1.67.
• [6] A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts.J Dent Res. 2017 Oct;96(11):1322-1329. doi: 10.1177/0022034517716914. Epub 2017 Jun 29.
• [7] The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodeling.Genes Dev. 2012 Oct 15;26(20):2299-310. doi: 10.1101/gad.200436.112.
• [8] Human Skeletal Muscle Cells Derived from the Orbicularis Oculi Have Regenerative Capacity for Duchenne Muscular Dystrophy.Int J Mol Sci. 2019 Jul 14;20(14):3456. doi: 10.3390/ijms20143456.
• [9] PAX7 target gene repression is a superior FSHD biomarker than DUX4 target gene activation, associating with pathological severity and identifying FSHD at the single-cell level.Hum Mol Genet. 2019 Jul 1;28(13):2224-2236. doi: 10.1093/hmg/ddz043.
• [10] Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.Nat Commun. 2017 Feb 24;8:14364. doi: 10.1038/ncomms14364.
• [11] Evidence that general genomic hypomethylation and focal hypermethylation are two independent molecular events of non-Hodgkin's lymphoma.Oncol Res. 2004;14(7-8):399-405. doi: 10.3727/0965040041292323.
• [12] Inflammatory leiomyosarcoma is a distinct tumor characterized by near-haploidization, few somatic mutations, and a primitive myogenic gene expression signature.Mod Pathol. 2018 Jan;31(1):93-100. doi: 10.1038/modpathol.2017.113. Epub 2017 Sep 8.
• [13] Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy. Genet Med. 2019 Nov;21(11):2521-2531. doi: 10.1038/s41436-019-0532-z. Epub 2019 May 16.
• [14] Characterization of the alternate allelic forms of human PAX7.Mamm Genome. 2000 Apr;11(4):332-7. doi: 10.1007/s003350010061.
• [15] Immunohistochemical and molecular genetic approaches to soft tissue tumor diagnosis: a primer.Semin Oncol. 1997 Oct;24(5):515-25.
• [16] Abnormalities in early markers of muscle involvement support a delay in myogenesis in spinal muscular atrophy.J Neuropathol Exp Neurol. 2014 Jun;73(6):559-67. doi: 10.1097/NEN.0000000000000078.
• [17] Zika virus induces abnormal cranial osteogenesis by negatively affecting cranial neural crest development.Infect Genet Evol. 2019 Apr;69:176-189. doi: 10.1016/j.meegid.2019.01.023. Epub 2019 Jan 19.
• [18] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [19] Myoblast replication is reduced in the IUGR fetus despite maintained proliferative capacity in vitro.J Endocrinol. 2017 Mar;232(3):475-491. doi: 10.1530/JOE-16-0123. Epub 2017 Jan 4.
• [20] Limitations of the Pax7-creER(T2) transgene for driving deletion of Nf1 in adult mouse muscle.Int J Dev Biol. 2017;61(8-9):531-536. doi: 10.1387/ijdb.170182as.
• [21] Bone Morphogenetic Proteins and myostatin pathways: key mediator of human sarcopenia.J Transl Med. 2017 Feb 15;15(1):34. doi: 10.1186/s12967-017-1143-6.
• [22] Rhabdomyosarcomadiagnosed in the first year of life: Localized, metastatic, and relapsed disease. Outcome data from five trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS).Pediatr Blood Cancer. 2019 Jun;66(6):e27652. doi: 10.1002/pbc.27652. Epub 2019 Feb 14.
• [23] MMP-1 Over-expression Promotes Malignancy and Stem-Like Properties of Human Osteosarcoma MG-63 Cells In Vitro.Curr Med Sci. 2018 Oct;38(5):809-817. doi: 10.1007/s11596-018-1947-5. Epub 2018 Dec 29.
• [24] Aberrant PAX3 and PAX7 expression. A link to the metastatic potential of embryonal rhabdomyosarcoma and cutaneous malignant melanoma?.Histol Histopathol. 2003 Apr;18(2):529-39. doi: 10.14670/HH-18.529.
• [25] Muscle satellite cells are functionally impaired in myasthenia gravis: consequences on muscle regeneration.Acta Neuropathol. 2017 Dec;134(6):869-888. doi: 10.1007/s00401-017-1754-2. Epub 2017 Jul 29.
• [26] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [27] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [28] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [29] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [30] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [31] 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.
• [32] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [33] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [34] 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.
• [35] 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.
• [36] 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.