Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3D62WB)

• DOT Name: Achaete-scute homolog 2 (ASCL2)
• Synonyms: ASH-2; hASH2; Class A basic helix-loop-helix protein 45; bHLHa45; Mash2
• Gene Name: ASCL2
• Related Disease:
  Adenoma
  Advanced cancer
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Colitis
  Colonic neoplasm
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Multiple sclerosis
  Neoplasm
  Non-insulin dependent diabetes
  Sjogren syndrome
  Stomach cancer
  Choriocarcinoma
  Gastric cancer
  Gastric neoplasm
  Hydatidiform mole
  Rectal carcinoma
  Autoimmune disease
• UniProt ID: ASCL2_HUMAN
• Pfam ID: PF00010
• Sequence:
  MDGGTLPRSAPPAPPVPVGCAARRRPASPELLRCSRRRRPATAETGGGAAAVARRNERER
  NRVKLVNLGFQALRQHVPHGGASKKLSKVETLRSAVEYIRALQRLLAEHDAVRNALAGGL
  RPQAVRPSAPRGPPGTTPVAASPSRASSSPGRGGSSEPGSPRSAYSSDDSGCEGALSPAE
  RELLDFSSWLGGY
• Function: Transcription factor. Binds to E-box motifs 5'-CANNTG-3' in the regulatory elements of target genes, probably as a heterodimer with another basic helix-loop-helix (bHLH) protein such as the transcription factor TCF3. May bind both open and closed chromatin, acting as a pioneer transcription factor to allow other factors to bind and activate lineage-specific genes. Required during post-implantation development for the generation of some differentiated trophoblast cell types. Transcriptional activity of ASCL2 may be antagonised in a subset of trophoblast cells by bHLH transcription factor HAND1, perhaps by competing for dimerization with other bHLH proteins. Involved in differentiation and function of follicular T-helper (Tfh) cells, thereby playing a role in germinal center responses; probably modulates expression of genes involved in Tfh cell function, such as BCL6. May also act as a suppressor of Th1-, Th2- and Th17-cell differentiation. Induces the formation of stem cells in intestinal crypts in vitro, synergistically activating transcription of target genes, such as SOX9, together with TCF4/beta-catenin. May form a bistable transcriptional switch, controlling expression of its own gene together with Wnt/R-spondin signaling, and thereby maintaining stem cell characteristics. Modulates expression of target genes, including perhaps down-regulating EGR1/Krox24 and chemokine CXCL10/Mob-1 and up-regulating CXCR4 and CDKN1C/p57kip2, in Schwann cells. May play a role in reducing proliferation of Schwann cells, perhaps acting via modulation of expression of CDKN1C. May be dispensable for blastocyst formation and later embryonic function. May be involved in the determination of neuronal precursors.
• Tissue Specificity: Expressed in the placenta at a stage between the first and second trimesters and when it matures, at about 32-36 weeks . Expressed in the extravillous trophoblasts, the intermediate trophoblasts, and at lower levels in the cytotrophoblasts and stroma of chorionic villi of the developing placenta . Expressed in follicular T-helper (Tfh) cells .

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Colitis	DISAF7DD	Strong	Altered Expression	[6]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[6]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[12]
Sjogren syndrome	DISUBX7H	Strong	Altered Expression	[13]
Stomach cancer	DISKIJSX	Strong	Biomarker	[14]
Choriocarcinoma	DISDBVNL	moderate	Altered Expression	[15]
Gastric cancer	DISXGOUK	moderate	Biomarker	[14]
Gastric neoplasm	DISOKN4Y	moderate	Altered Expression	[14]
Hydatidiform mole	DISKNP7O	moderate	Altered Expression	[15]
Rectal carcinoma	DIS8FRR7	moderate	Altered Expression	[8]
Autoimmune disease	DISORMTM	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Achaete-scute homolog 2 (ASCL2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Achaete-scute homolog 2 (ASCL2).	[21]

6 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 Achaete-scute homolog 2 (ASCL2).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Achaete-scute homolog 2 (ASCL2).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Achaete-scute homolog 2 (ASCL2).	[19]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the expression of Achaete-scute homolog 2 (ASCL2).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Achaete-scute homolog 2 (ASCL2).	[22]
Linoleic acid	DMDGPY9	Investigative	Linoleic acid decreases the expression of Achaete-scute homolog 2 (ASCL2).	[20]

References

• [1] In situ validation of an intestinal stem cell signature in colorectal cancer.Gut. 2013 Jul;62(7):1012-23. doi: 10.1136/gutjnl-2011-301195. Epub 2012 May 25.
• [2] SMYD3 controls a Wnt-responsive epigenetic switch for ASCL2 activation and cancer stem cell maintenance.Cancer Lett. 2018 Aug 28;430:11-24. doi: 10.1016/j.canlet.2018.05.003. Epub 2018 May 8.
• [3] Achaete-scute complex homologue 2 accelerates the development of Sjgren's syndrome-like disease in the NOD/ShiLtJ mouse.Immunol Lett. 2017 Oct;190:26-33. doi: 10.1016/j.imlet.2017.07.010. Epub 2017 Jul 17.
• [4] Elevated ASCL2 expression in breast cancer is associated with the poor prognosis of patients.Am J Cancer Res. 2017 Apr 1;7(4):955-961. eCollection 2017.
• [5] 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.
• [6] Ascl2 facilitates IL-10 production in Th17 cells to restrain their pathogenicity in inflammatory bowel disease.Biochem Biophys Res Commun. 2019 Mar 12;510(3):435-441. doi: 10.1016/j.bbrc.2019.01.123. Epub 2019 Feb 2.
• [7] Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.Carcinogenesis. 2004 Aug;25(8):1495-505. doi: 10.1093/carcin/bgh155. Epub 2004 Apr 1.
• [8] Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer.Ann Surg Oncol. 2019 May;26(5):1401-1411. doi: 10.1245/s10434-019-07172-7. Epub 2019 Jan 31.
• [9] Discovery and validation of methylation markers for endometrial cancer.Int J Cancer. 2014 Oct 15;135(8):1860-8. doi: 10.1002/ijc.28843. Epub 2014 Mar 31.
• [10] Protective C allele of the single-nucleotide polymorphism rs1335532 is associated with strong binding of Ascl2 transcription factor and elevated CD58 expression in B-cells.Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3211-3220. doi: 10.1016/j.bbadis.2018.07.008. Epub 2018 Jul 10.
• [11] Self-antigen MASH2 combined with the AS15 immunostimulant induces tumor protection in colorectal cancer mouse models.PLoS One. 2019 Jan 25;14(1):e0210261. doi: 10.1371/journal.pone.0210261. eCollection 2019.
• [12] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [13] Achaete-Scute Homologue 2-Regulated Follicular Helper T Cells Promote Autoimmunity in a Murine Model for Sjgren Syndrome.Am J Pathol. 2019 Dec;189(12):2414-2427. doi: 10.1016/j.ajpath.2019.08.008. Epub 2019 Sep 17.
• [14] ASCL2 expression contributes to gastric tumor migration and invasion by downregulating miR223 and inducing EMT.Mol Med Rep. 2018 Oct;18(4):3751-3759. doi: 10.3892/mmr.2018.9363. Epub 2018 Aug 8.
• [15] Detection of HASH2 (ASCL2) gene expression in gestational trophoblastic disease.J Reprod Med. 2006 Nov;51(11):892-6.
• [16] 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.
• [17] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [20] Expression of cFABP and PPAR in trophoblast cells: effect of PPAR ligands on linoleic acid uptake and differentiation. Biochim Biophys Acta. 2005 Feb 21;1687(1-3):181-94. doi: 10.1016/j.bbalip.2004.11.017.
• [21] 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.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.