Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKNK5H0)

DOT Name	Homeobox protein Hox-A9 (HOXA9)
Synonyms	Homeobox protein Hox-1G
Gene Name	HOXA9
Related Disease	Ovarian cancer ( ) Adult glioblastoma ( ) Advanced cancer ( ) Blast phase chronic myelogenous leukemia, BCR-ABL1 positive ( ) Bone osteosarcoma ( ) Breast cancer ( ) Breast carcinoma ( ) Carcinoma ( ) Cervical cancer ( ) Cervical carcinoma ( ) Colorectal carcinoma ( ) Epithelial ovarian cancer ( ) Glioma ( ) Hepatocellular carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Melanoma ( ) Meningioma ( ) Myelodysplastic syndrome ( ) Myeloid leukaemia ( ) Myeloproliferative neoplasm ( ) Non-small-cell lung cancer ( ) Osteosarcoma ( ) Ovarian neoplasm ( ) Precancerous condition ( ) Prostate cancer ( ) Prostate carcinoma ( ) Squamous cell carcinoma ( ) T-cell acute lymphoblastic leukaemia ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Acute lymphocytic leukaemia ( ) Chronic obstructive pulmonary disease ( ) Glioblastoma multiforme ( ) Head-neck squamous cell carcinoma ( ) Lung adenocarcinoma ( ) Metastatic malignant neoplasm ( ) Childhood acute lymphoblastic leukemia ( ) Childhood myelodysplastic syndrome ( ) Clubfoot ( ) Acute leukaemia ( ) Acute monocytic leukemia ( ) Acute undifferentiated leukemia ( ) Chromosomal disorder ( ) Cutaneous squamous cell carcinoma ( )
UniProt ID	HXA9_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00046 ; PF04617
Sequence	MATTGALGNYYVDSFLLGADAADELSVGRYAPGTLGQPPRQAATLAEHPDFSPCSFQSKA TVFGASWNPVHAAGANAVPAAVYHHHHHHPYVHPQAPVAAAAPDGRYMRSWLEPTPGALS FAGLPSSRPYGIKPEPLSARRGDCPTLDTHTLSLTDYACGSPPVDREKQPSEGAFSENNA ENESGGDKPPIDPNNPAANWLHARSTRKKRCPYTKHQTLELEKEFLFNMYLTRDRRYEVA RLLNLTERQVKIWFQNRRMKMKKINKDRAKDE
Function	Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Required for induction of SELE/E-selectin and VCAM1 on the endothelial cells surface at sites of inflammation. Positively regulates EIF4E-mediated mRNA nuclear export and also increases the translation efficiency of ODC mRNA in the cytoplasm by competing with factors which repress EIF4E activity such as PRH.
KEGG Pathway	Transcriptio.l misregulation in cancer (hsa05202 )

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Genetic Variation	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[8]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[13]
Lung carcinoma	DISTR26C	Strong	Biomarker	[13]
Melanoma	DIS1RRCY	Strong	Biomarker	[14]
Meningioma	DISPT4TG	Strong	Biomarker	[15]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[16]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[17]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Genetic Variation	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[13]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Precancerous condition	DISV06FL	Strong	Biomarker	[19]
Prostate cancer	DISF190Y	Strong	Biomarker	[20]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[20]
Squamous cell carcinoma	DISQVIFL	Strong	Posttranslational Modification	[21]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[22]
Urinary bladder cancer	DISDV4T7	Strong	Posttranslational Modification	[23]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[23]
Acute lymphocytic leukaemia	DISPX75S	moderate	Biomarker	[24]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[25]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[2]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[26]
Lung adenocarcinoma	DISD51WR	moderate	Posttranslational Modification	[27]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[28]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Disputed	Biomarker	[24]
Childhood myelodysplastic syndrome	DISMN80I	Disputed	Genetic Variation	[29]
Clubfoot	DISLXT4S	Disputed	Genetic Variation	[30]
Acute leukaemia	DISDQFDI	Limited	Altered Expression	[31]
Acute monocytic leukemia	DIS28NEL	Limited	Altered Expression	[32]
Acute undifferentiated leukemia	DISJ4SSG	Limited	Biomarker	[33]
Chromosomal disorder	DISM5BB5	Limited	Altered Expression	[34]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[35]
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⏷ Show the Full List of 45 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

8 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 Homeobox protein Hox-A9 (HOXA9).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Homeobox protein Hox-A9 (HOXA9).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein Hox-A9 (HOXA9).	[36]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Homeobox protein Hox-A9 (HOXA9).	[38]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Homeobox protein Hox-A9 (HOXA9).	[39]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Homeobox protein Hox-A9 (HOXA9).	[40]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein Hox-A9 (HOXA9).	[42]
EPZ-004777	DMLN4V5	Investigative	EPZ-004777 decreases the expression of Homeobox protein Hox-A9 (HOXA9).	[43]
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⏷ Show the Full List of 8 Drug(s)

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-A9 (HOXA9).	[41]
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References

1	HOXA9 promotes homotypic and heterotypic cell interactions that facilitate ovarian cancer dissemination via its induction of P-cadherin.Mol Cancer. 2014 Jul 14;13:170. doi: 10.1186/1476-4598-13-170.
2	A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide.Oncotarget. 2015 Apr 10;6(10):7657-74. doi: 10.18632/oncotarget.3150.
3	Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia.Cancers (Basel). 2019 Jun 17;11(6):837. doi: 10.3390/cancers11060837.
4	NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis.Br J Haematol. 2011 Oct;155(2):167-81. doi: 10.1111/j.1365-2141.2011.08810.x. Epub 2011 Aug 2.
5	MicroRNA?73 targets HOXA9 to inhibit the aggressive phenotype of osteosarcoma by deactivating the Wnt/catenin pathway.Int J Oncol. 2019 May;54(5):1809-1820. doi: 10.3892/ijo.2019.4735. Epub 2019 Feb 28.
6	A long-range interactive DNA methylation marker panel for the promoters of HOXA9 and HOXA10 predicts survival in breast cancer patients.Clin Epigenetics. 2017 Jul 24;9:73. doi: 10.1186/s13148-017-0373-z. eCollection 2017.
7	Comparative transcriptome analysis of sinonasal inverted papilloma and associated squamous cell carcinoma: Out-HOXing developmental genes.Head Neck. 2019 Sep;41(9):3090-3104. doi: 10.1002/hed.25795. Epub 2019 Apr 30.
8	HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes.Asian Pac J Cancer Prev. 2016;17(3):1037-47. doi: 10.7314/apjcp.2016.17.3.1037.
9	Gene expression signatures for HOXA4, HOXA9, and HOXD10 reveal alterations in transcriptional regulatory networks in colon cancer.J Cell Physiol. 2019 Aug;234(8):13042-13056. doi: 10.1002/jcp.27975. Epub 2018 Dec 14.
10	Overexpression of microRNA-196b Accelerates Invasiveness of Cancer Cells in Recurrent Epithelial Ovarian Cancer Through Regulation of Homeobox A9.Cancer Genomics Proteomics. 2017 Mar-Apr;14(2):137-141. doi: 10.21873/cgp.20026.
11	MiR-638 serves as a tumor suppressor by targeting HOXA9 in glioma.Eur Rev Med Pharmacol Sci. 2018 Nov;22(22):7798-7806. doi: 10.26355/eurrev_201811_16404.
12	Frequent methylation of HOXA9 gene in tumor tissues and plasma samples from human hepatocellular carcinomas.Clin Chem Lab Med. 2014 Aug;52(8):1235-45. doi: 10.1515/cclm-2013-0780.
13	Recombinant cell-permeable HOXA9 protein inhibits NSCLC cell migration and invasion.Cell Oncol (Dordr). 2019 Jun;42(3):275-285. doi: 10.1007/s13402-019-00424-4. Epub 2019 Jan 29.
14	Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.Cancer Res. 2006 Jun 15;66(12):6080-6. doi: 10.1158/0008-5472.CAN-06-0157.
15	Meningioma 1 is indispensable for mixed lineage leukemia-rearranged acute myeloid leukemia.Haematologica. 2020 May;105(5):1294-1305. doi: 10.3324/haematol.2018.211201. Epub 2019 Aug 14.
16	Myelodysplastic syndromes are induced by histone methylationaltering ASXL1 mutations.J Clin Invest. 2013 Nov;123(11):4627-40. doi: 10.1172/JCI70739.
17	Regulation of HOXA9 activity by predominant expression of DACH1 against C/EBP and GATA-1 in myeloid leukemia with MLL-AF9.Biochem Biophys Res Commun. 2012 Sep 28;426(3):299-305. doi: 10.1016/j.bbrc.2012.08.048. Epub 2012 Aug 17.
18	The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.Blood. 2012 Nov 8;120(19):4006-17. doi: 10.1182/blood-2011-02-334722. Epub 2012 Aug 28.
19	HOXA9 mediates and marks premalignant compartment size expansion in colonic adenomas.Carcinogenesis. 2019 Dec 31;40(12):1514-1524. doi: 10.1093/carcin/bgz038.
20	TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis.Cancer Res. 2017 Jun 15;77(12):3181-3193. doi: 10.1158/0008-5472.CAN-16-2797. Epub 2017 May 8.
21	Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis.BMC Cancer. 2014 May 21;14:353. doi: 10.1186/1471-2407-14-353.
22	HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development.Cancer Discov. 2018 May;8(5):616-631. doi: 10.1158/2159-8290.CD-17-0583. Epub 2018 Mar 1.
23	An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.Biomolecules. 2016 Sep 2;6(3):37. doi: 10.3390/biom6030037.
24	AAV8 vector expressing IL24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice.Blood. 2012 Jan 5;119(1):64-71. doi: 10.1182/blood-2011-05-354050. Epub 2011 Oct 24.
25	Relationship between COPD and polymorphisms of HOX-1 and mEPH in a Chinese population.Oncol Rep. 2007 Feb;17(2):483-8.
26	The clinical significance of HOXA9 promoter hypermethylation in head and neck squamous cell carcinoma.J Clin Lab Anal. 2019 Jun;33(5):e22873. doi: 10.1002/jcla.22873. Epub 2019 Mar 6.
27	HOXA9 methylation and blood vessel invasion in FFPE tissues for prognostic stratification of stage I lung adenocarcinoma patients.Lung Cancer. 2018 Aug;122:151-159. doi: 10.1016/j.lungcan.2018.05.021. Epub 2018 May 22.
28	miR-133b suppresses metastasis by targeting HOXA9 in human colorectal cancer.Oncotarget. 2017 Jul 12;8(38):63935-63948. doi: 10.18632/oncotarget.19212. eCollection 2017 Sep 8.
29	NUP98 dysregulation in myeloid leukemogenesis.Ann N Y Acad Sci. 2007 Jun;1106:114-42. doi: 10.1196/annals.1392.019. Epub 2007 Apr 18.
30	HOXA9 rs3801776 G>A polymorphism increases congenital talipes equinovarus risk in a Chinese population.J Gene Med. 2019 Oct;21(10):e3119. doi: 10.1002/jgm.3119. Epub 2019 Aug 30.
31	HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis.Cancer Cell. 2018 Oct 8;34(4):643-658.e5. doi: 10.1016/j.ccell.2018.08.018. Epub 2018 Sep 27.
32	Aberrant Expression of HOXA5 and HOXA9 in AML.Asian Pac J Cancer Prev. 2015;16(9):3941-4. doi: 10.7314/apjcp.2015.16.9.3941.
33	PBX3 is essential for leukemia stem cell maintenance in MLL-rearranged leukemia.Int J Cancer. 2017 Jul 15;141(2):324-335. doi: 10.1002/ijc.30739. Epub 2017 May 8.
34	Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality.Oncogene. 2001 Feb 15;20(7):874-8. doi: 10.1038/sj.onc.1204174.
35	HOXA9 Transcriptionally Promotes Apoptosis and Represses Autophagy by Targeting NF-B in Cutaneous Squamous Cell Carcinoma.Cells. 2019 Oct 31;8(11):1360. doi: 10.3390/cells8111360.
36	HOXA9 is critical in the proliferation, differentiation, and malignancy of leukaemia cells both in vitro and in vivo. Cell Biochem Funct. 2017 Oct;35(7):433-440. doi: 10.1002/cbf.3293. Epub 2017 Sep 29.
37	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.
38	The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
39	Endocrine regulation of HOX genes. Endocr Rev. 2006 Jun;27(4):331-55. doi: 10.1210/er.2005-0018. Epub 2006 Apr 21.
40	Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
41	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.
42	CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
43	DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia. Blood. 2016 Aug 18;128(7):971-81. doi: 10.1182/blood-2015-11-684225. Epub 2016 Jun 22.