Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3HG324)

• DOT Name: Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L)
• Synonyms: ASH2-like protein
• Gene Name: ASH2L
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Carcinoma
  Schizophrenia
  Hepatocellular carcinoma
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
• UniProt ID: ASH2L_HUMAN
• PDB ID: 3RSN; 3S32; 3TOJ; 4RIQ; 4X8N; 4X8P; 5F6K; 5F6L; 6E2H; 6KIU; 6KIV; 6KIW; 6KIX; 6KIZ; 6PWV; 6W5I; 6W5M; 6W5N; 7BRE; 7MBM; 7MBN; 7UD5; 7W67; 7W6A; 7W6I; 7W6J; 7W6L
• Pfam ID: PF21198 ; PF21257 ; PF00622
• Sequence:
  MAAAGAGPGQEAGAGPGPGAVANATGAEEGEMKPVAAGAAAPPGEGISAAPTVEPSSGEA
  EGGEANLVDVSGGLETESSNGKDTLEGAGDTSEVMDTQAGSVDEENGRQLGEVELQCGIC
  TKWFTADTFGIDTSSCLPFMTNYSFHCNVCHHSGNTYFLRKQANLKEMCLSALANLTWQS
  RTQDEHPKTMFSKDKDIIPFIDKYWECMTTRQRPGKMTWPNNIVKTMSKERDVFLVKEHP
  DPGSKDPEEDYPKFGLLDQDLSNIGPAYDNQKQSSAVSTSGNLNGGIAAGSSGKGRGAKR
  KQQDGGTTGTTKKARSDPLFSAQRLPPHGYPLEHPFNKDGYRYILAEPDPHAPDPEKLEL
  DCWAGKPIPGDLYRACLYERVLLALHDRAPQLKISDDRLTVVGEKGYSMVRASHGVRKGA
  WYFEITVDEMPPDTAARLGWSQPLGNLQAPLGYDKFSYSWRSKKGTKFHQSIGKHYSSGY
  GQGDVLGFYINLPEDTETAKSLPDTYKDKALIKFKSYLYFEEKDFVDKAEKSLKQTPHSE
  IIFYKNGVNQGVAYKDIFEGVYFPAISLYKSCTVSINFGPCFKYPPKDLTYRPMSDMGWG
  AVVEHTLADVLYHVETEVDGRRSPPWEP
• Function: Transcriptional regulator. Component or associated component of some histone methyltransferase complexes which regulates transcription through recruitment of those complexes to gene promoters. Component of the Set1/Ash2 histone methyltransferase (HMT) complex, a complex that specifically methylates 'Lys-4' of histone H3, but not if the neighboring 'Lys-9' residue is already methylated. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. May play a role in hematopoiesis. In association with RBBP5 and WDR5, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B.
• Tissue Specificity: Ubiquitously expressed. Predominantly expressed in adult heart and testis and fetal lung and liver, with barely detectable expression in adult lung, liver, kidney, prostate, and peripheral leukocytes.
• KEGG Pathway: Cushing syndrome (hsa04934)
• Reactome Pathway:
  PKMTs methylate histone lysines (R-HSA-3214841)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[4]
Matthew-Wood syndrome	DISA7HR7	Disputed	Biomarker	[5]
Pancreatic ductal carcinoma	DIS26F9Q	Disputed	Biomarker	[5]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[15]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[17]

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 affects the methylation of Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L).	[16]

References

• [1] Low expression of ASH2L protein correlates with a favorable outcome in acute myeloid leukemia.Leuk Lymphoma. 2017 May;58(5):1207-1218. doi: 10.1080/10428194.2016.1235272. Epub 2016 Oct 13.
• [2] H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1.Hum Pathol. 2010 Feb;41(2):181-9. doi: 10.1016/j.humpath.2009.08.007. Epub 2009 Nov 6.
• [3] Prenatal MAM administration affects histone H3 methylation in postnatal life in the rat medial prefrontal cortex.Eur Neuropsychopharmacol. 2014 Feb;24(2):271-89. doi: 10.1016/j.euroneuro.2013.05.013. Epub 2013 Aug 8.
• [4] ZNF479 downregulates metallothionein-1 expression by regulating ASH2L and DNMT1 in hepatocellular carcinoma.Cell Death Dis. 2019 May 28;10(6):408. doi: 10.1038/s41419-019-1651-9.
• [5] Circ-ASH2L promotes tumor progression by sponging miR-34a to regulate Notch1 in pancreatic ductal adenocarcinoma.J Exp Clin Cancer Res. 2019 Nov 12;38(1):466. doi: 10.1186/s13046-019-1436-0.
• [6] MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription.Oncogene. 2015 Oct 29;34(44):5570-81. doi: 10.1038/onc.2015.14. Epub 2015 Mar 9.
• [7] Absent, small or homeotic 2-like protein (ASH2L) enhances the transcription of the estrogen receptor gene through GATA-binding protein 3 (GATA3).J Biol Chem. 2014 Nov 7;289(45):31373-81. doi: 10.1074/jbc.M114.579839. Epub 2014 Sep 25.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [14] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [15] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [16] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [17] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.