Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT52AVNA)

• DOT Name: Homeobox protein Hox-C13 (HOXC13)
• Synonyms: Homeobox protein Hox-3G
• Gene Name: HOXC13
• Related Disease:
  Ectodermal dysplasia 9, hair/nail type
  Acute myelogenous leukaemia
  Acute myelomonocytic leukemia M4
  Advanced cancer
  Cerebral infarction
  Esophageal squamous cell carcinoma
  Hydatidiform mole
  Liposarcoma
  Lung adenocarcinoma
  Neoplasm
  Colon cancer
  Colon carcinoma
  Ectodermal dysplasia
  Pure hair and nail ectodermal dysplasia
  Hypotrichosis
  Leukoplakia
• UniProt ID: HXC13_HUMAN
• Pfam ID: PF00046 ; PF12284
• Sequence:
  MTTSLLLHPRWPESLMYVYEDSAAESGIGGGGGGGGGGTGGAGGGCSGASPGKAPSMDGL
  GSSCPASHCRDLLPHPVLGRPPAPLGAPQGAVYTDIPAPEAARQCAPPPAPPTSSSATLG
  YGYPFGGSYYGCRLSHNVNLQQKPCAYHPGDKYPEPSGALPGDDLSSRAKEFAFYPSFAS
  SYQAMPGYLDVSVVPGISGHPEPRHDALIPVEGYQHWALSNGWDSQVYCSKEQSQSAHLW
  KSPFPDVVPLQPEVSSYRRGRKKRVPYTKVQLKELEKEYAASKFITKEKRRRISATTNLS
  ERQVTIWFQNRRVKEKKVVSKSKAPHLHST
• Function: Transcription factor which plays a role in hair follicle differentiation. Regulates FOXQ1 expression and that of other hair-specific genes.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ectodermal dysplasia 9, hair/nail type	DIST0X30	Definitive	Autosomal recessive	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[2]
Acute myelomonocytic leukemia M4	DISRRMV2	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Hydatidiform mole	DISKNP7O	Strong	Altered Expression	[7]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[8]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Colon cancer	DISVC52G	moderate	Biomarker	[11]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[11]
Ectodermal dysplasia	DISLRS4M	moderate	Genetic Variation	[12]
Pure hair and nail ectodermal dysplasia	DIS83WTF	Supportive	Autosomal dominant	[13]
Hypotrichosis	DISSW933	Limited	Biomarker	[12]
Leukoplakia	DIST3QD3	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Homeobox protein Hox-C13 (HOXC13).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein Hox-C13 (HOXC13).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Homeobox protein Hox-C13 (HOXC13).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Homeobox protein Hox-C13 (HOXC13).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Homeobox protein Hox-C13 (HOXC13).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein Hox-C13 (HOXC13).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Homeobox protein Hox-C13 (HOXC13).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Homeobox protein Hox-C13 (HOXC13).	[23]

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 decreases the methylation of Homeobox protein Hox-C13 (HOXC13).	[20]

References

• [1] A homozygous frameshift mutation in the HOXC13 gene underlies pure hair and nail ectodermal dysplasia in a Syrian family. Hum Mutat. 2013 Apr;34(4):578-81. doi: 10.1002/humu.22271. Epub 2013 Mar 5.
• [2] 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.
• [3] Acute myeloid leukemia with NUP98-HOXC13 fusion and FLT3 internal tandem duplication mutation: case report and literature review.Cancer Genet Cytogenet. 2009 Sep;193(2):98-103. doi: 10.1016/j.cancergencyto.2009.03.007.
• [4] Human homeobox gene HOXC13 is the partner of NUP98 in adult acute myeloid leukemia with t(11;12)(p15;q13).Genes Chromosomes Cancer. 2003 Apr;36(4):420-3. doi: 10.1002/gcc.10182.
• [5] Vascular endothelial growth factor aggravates cerebral ischemia and reperfusion-induced blood-brain-barrier disruption through regulating LOC102640519/HOXC13/ZO-1 signaling.Exp Cell Res. 2018 Aug 15;369(2):275-283. doi: 10.1016/j.yexcr.2018.05.029. Epub 2018 May 26.
• [6] HOXC13 promotes proliferation of esophageal squamous cell carcinoma via repressing transcription of CASP3.Cancer Sci. 2018 Feb;109(2):317-329. doi: 10.1111/cas.13453. Epub 2017 Dec 20.
• [7] The three most downstream genes of the Hox-3 cluster are expressed in human extraembryonic tissues including trophoblast of androgenetic origin.Development. 1990 Mar;108(3):471-7. doi: 10.1242/dev.108.3.471.
• [8] Hyperexpression of HOXC13, located in the 12q13 chromosomal region, in welldifferentiated and dedifferentiated human liposarcomas.Oncol Rep. 2013 Dec;30(6):2579-86. doi: 10.3892/or.2013.2760. Epub 2013 Oct 1.
• [9] HOXC13 promotes proliferation of lung adenocarcinoma via modulation of CCND1 and CCNE1.Am J Cancer Res. 2017 Sep 1;7(9):1820-1834. eCollection 2017.
• [10] Posterior HOX genes and HOTAIR expression in the proximal and distal colon cancer pathogenesis.J Transl Med. 2018 Dec 12;16(1):350. doi: 10.1186/s12967-018-1725-y.
• [11] Candidate genes involved in metastasis of colon cancer identified by integrated analysis.Cancer Med. 2019 May;8(5):2338-2347. doi: 10.1002/cam4.2071. Epub 2019 Mar 18.
• [12] The disrupted balance between hair follicles and sebaceous glands in Hoxc13-ablated rabbits.FASEB J. 2019 Jan;33(1):1226-1234. doi: 10.1096/fj.201800928RR. Epub 2018 Aug 20.
• [13] Loss-of-function mutations in HOXC13 cause pure hair and nail ectodermal dysplasia. Am J Hum Genet. 2012 Nov 2;91(5):906-11. doi: 10.1016/j.ajhg.2012.08.029. Epub 2012 Oct 11.
• [14] Chromosomal Alterations and Gene Expression Changes Associated with the Progression of Leukoplakia to Advanced Gingivobuccal Cancer.Transl Oncol. 2017 Jun;10(3):396-409. doi: 10.1016/j.tranon.2017.03.008. Epub 2017 Apr 21.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [18] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] 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.
• [21] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [22] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.