Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI9TWY4)

DOT Name	Hypermethylated in cancer 1 protein (HIC1)
Synonyms	Hic-1; Zinc finger and BTB domain-containing protein 29
Gene Name	HIC1
Related Disease	Hepatocellular carcinoma ( ) Lung adenocarcinoma ( ) Neuroblastoma ( ) Ovarian cancer ( ) Acute myelogenous leukaemia ( ) Adenocarcinoma ( ) Advanced cancer ( ) Bone osteosarcoma ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Cervical cancer ( ) Clear cell renal carcinoma ( ) Colon cancer ( ) Colon carcinoma ( ) Digestive system neoplasm ( ) Ependymoma ( ) Esophageal squamous cell carcinoma ( ) Gastric cancer ( ) Glioma ( ) Lung cancer ( ) Lung carcinoma ( ) Medulloblastoma ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Osteosarcoma ( ) Prostate cancer ( ) Prostate carcinoma ( ) Renal cell carcinoma ( ) Squamous cell carcinoma ( ) Stomach cancer ( ) Venous thromboembolism ( ) Carcinoma ( ) Polyp ( ) Age-related macular degeneration ( ) Beckwith-Wiedemann syndrome ( ) Bladder cancer ( ) Cervical carcinoma ( ) Colorectal carcinoma ( ) Leukemia ( ) Pancreatic cancer ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( )
UniProt ID	HIC1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00651 ; PF00096
Sequence	MTFPEADILLKSGECAGQTMLDTMEAPGHSRQLLLQLNNQRTKGFLCDVIIVVQNALFRA HKNVLAASSAYLKSLVVHDNLLNLDHDMVSPAVFRLVLDFIYTGRLADGAEAAAAAAVAP GAEPSLGAVLAAASYLQIPDLVALCKKRLKRHGKYCHLRGGGGGGGGYAPYGRPGRGLRA ATPVIQACYPSPVGPPPPPAAEPPSGPEAAVNTHCAELYASGPGPAAALCASERRCSPLC GLDLSKKSPPGSAAPERPLAERELPPRPDSPPSAGPAAYKEPPLALPSLPPLPFQKLEEA APPSDPFRGGSGSPGPEPPGRPDGPSLLYRWMKHEPGLGSYGDELGRERGSPSERCEERG GDAAVSPGGPPLGLAPPPRYPGSLDGPGAGGDGDDYKSSSEETGSSEDPSPPGGHLEGYP CPHLAYGEPESFGDNLYVCIPCGKGFPSSEQLNAHVEAHVEEEEALYGRAEAAEVAAGAA GLGPPFGGGGDKVAGAPGGLGELLRPYRCASCDKSYKDPATLRQHEKTHWLTRPYPCTIC GKKFTQRGTMTRHMRSHLGLKPFACDACGMRFTRQYRLTEHMRIHSGEKPYECQVCGGKF AQQRNLISHMKMHAVGGAAGAAGALAGLGGLPGVPGPDGKGKLDFPEGVFAVARLTAEQL SLKQQDKAAAAELLAQTTHFLHDPKVALESLYPLAKFTAELGLSPDKAAEVLSQGAHLAA GPDGRTIDRFSPT
Function	Transcriptional repressor. Recognizes and binds to the consensus sequence '5-[CG]NG[CG]GGGCA[CA]CC-3'. May act as a tumor suppressor. Involved in development of head, face, limbs and ventral body wall. Involved in down-regulation of SIRT1 and thereby is involved in regulation of p53/TP53-dependent apoptotic DNA-damage responses. The specific target gene promoter association seems to be depend on corepressors, such as CTBP1 or CTBP2 and MTA1. In cooperation with MTA1 (indicative for an association with the NuRD complex) represses transcription from CCND1/cyclin-D1 and CDKN1C/p57Kip2 specifically in quiescent cells. Involved in regulation of the Wnt signaling pathway probably by association with TCF7L2 and preventing TCF7L2 and CTNNB1 association with promoters of TCF-responsive genes. Seems to repress transcription from E2F1 and ATOH1 which involves ARID1A, indicative for the participation of a distinct SWI/SNF-type chromatin-remodeling complex. Probably represses transcription of ACKR3, FGFBP1 and EFNA1.
Tissue Specificity	Ubiquitously expressed with highest levels found in lung, colon, prostate, thymus, testis and ovary. Expression is absent or decreased in many tumor cells.
Reactome Pathway	SUMOylation of transcription factors (R-HSA-3232118 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Genetic Variation	[2]
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[3]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[5]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[10]
Cervical cancer	DISFSHPF	Strong	Biomarker	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Posttranslational Modification	[12]
Colon cancer	DISVC52G	Strong	Genetic Variation	[13]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[13]
Digestive system neoplasm	DISPOJCT	Strong	Biomarker	[14]
Ependymoma	DISUMRNZ	Strong	Genetic Variation	[15]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[16]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[17]
Glioma	DIS5RPEH	Strong	Biomarker	[18]
Lung cancer	DISCM4YA	Strong	Biomarker	[19]
Lung carcinoma	DISTR26C	Strong	Biomarker	[19]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[20]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[21]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[22]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[22]
Renal cell carcinoma	DISQZ2X8	Strong	Posttranslational Modification	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[23]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[17]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[24]
Carcinoma	DISH9F1N	moderate	Altered Expression	[25]
Polyp	DISRSLYF	moderate	Biomarker	[14]
Age-related macular degeneration	DIS0XS2C	Limited	Biomarker	[26]
Beckwith-Wiedemann syndrome	DISH15GR	Limited	Genetic Variation	[27]
Bladder cancer	DISUHNM0	Limited	Biomarker	[7]
Cervical carcinoma	DIST4S00	Limited	Biomarker	[28]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[29]
Leukemia	DISNAKFL	Limited	Genetic Variation	[30]
Pancreatic cancer	DISJC981	Limited	Biomarker	[31]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[7]
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⏷ Show the Full List of 43 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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 Hypermethylated in cancer 1 protein (HIC1).	[32]
Folic acid	DMEMBJC	Approved	Folic acid increases the methylation of Hypermethylated in cancer 1 protein (HIC1).	[39]
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14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hypermethylated in cancer 1 protein (HIC1).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hypermethylated in cancer 1 protein (HIC1).	[34]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Hypermethylated in cancer 1 protein (HIC1).	[35]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Hypermethylated in cancer 1 protein (HIC1).	[36]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Hypermethylated in cancer 1 protein (HIC1).	[37]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Hypermethylated in cancer 1 protein (HIC1).	[38]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Hypermethylated in cancer 1 protein (HIC1).	[40]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Hypermethylated in cancer 1 protein (HIC1).	[41]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Hypermethylated in cancer 1 protein (HIC1).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Hypermethylated in cancer 1 protein (HIC1).	[43]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hypermethylated in cancer 1 protein (HIC1).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hypermethylated in cancer 1 protein (HIC1).	[45]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Hypermethylated in cancer 1 protein (HIC1).	[46]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Hypermethylated in cancer 1 protein (HIC1).	[47]
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⏷ Show the Full List of 14 Drug(s)

References

1	Quantitative methylation analysis of multiple genes using methylation-sensitive restriction enzyme-based quantitative PCR for the detection of hepatocellular carcinoma.Exp Mol Pathol. 2011 Aug;91(1):455-60. doi: 10.1016/j.yexmp.2011.05.001. Epub 2011 May 11.
2	Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients.Neoplasia. 2009 Aug;11(8):763-70. doi: 10.1593/neo.09470.
3	Epigenetic alterations differ in phenotypically distinct human neuroblastoma cell lines.BMC Cancer. 2010 Jun 14;10:286. doi: 10.1186/1471-2407-10-286.
4	Methylation profile in benign, borderline and malignant ovarian tumors.J Cancer Res Clin Oncol. 2007 May;133(5):331-41. doi: 10.1007/s00432-006-0178-5. Epub 2006 Dec 20.
5	Detection of Novel t(12;17)(p12;p13) in Relapsed Refractory Acute Myeloid Leukemia by Anchored Multiplex PCR(AMP)-based Next-Generation Sequencing.Appl Immunohistochem Mol Morphol. 2019 Mar;27(3):e28-e31. doi: 10.1097/PAI.0000000000000477.
6	The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53.Oncogene. 2018 Apr;37(14):1939-1948. doi: 10.1038/s41388-017-0022-1. Epub 2018 Jan 25.
7	Hypermethylated in cancer 1 (HIC1) suppresses bladder cancer progression by targeting yes-associated protein (YAP) pathway.J Cell Biochem. 2019 Apr;120(4):6471-6481. doi: 10.1002/jcb.27938. Epub 2018 Nov 11.
8	Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target gene of HIC1 (hypermethylated in cancer 1).J Biol Chem. 2009 Jul 31;284(31):20927-35. doi: 10.1074/jbc.M109.022350. Epub 2009 Jun 12.
9	Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer.BMC Cancer. 2019 Dec 3;19(1):1180. doi: 10.1186/s12885-019-6333-6.
10	A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1.Oncogene. 2010 Apr 29;29(17):2467-76. doi: 10.1038/onc.2010.12. Epub 2010 Feb 15.
11	Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science.Gynecol Oncol. 2009 Feb;112(2):293-9. doi: 10.1016/j.ygyno.2008.10.012. Epub 2008 Dec 2.
12	Prognostic and diagnostic relevance of hypermethylated in cancer 1 (HIC1) CpG island methylation in renal cell carcinoma.Int J Oncol. 2012 May;40(5):1650-8. doi: 10.3892/ijo.2012.1367. Epub 2012 Feb 10.
13	Methylation of the Tumor Suppressor Genes HIC1 and RassF1A Clusters Independently From the Methylation of Polycomb Target Genes in Colon Cancer.Ann Surg Oncol. 2017 Feb;24(2):578-585. doi: 10.1245/s10434-015-5024-z. Epub 2015 Dec 15.
14	Loss of a single Hic1 allele accelerates polyp formation in Apc(716) mice.Oncogene. 2011 Jun 9;30(23):2659-69. doi: 10.1038/onc.2010.633. Epub 2011 Feb 7.
15	Genetic differences on intracranial versus spinal cord ependymal tumors: a meta-analysis of genetic researches.Eur Spine J. 2016 Dec;25(12):3942-3951. doi: 10.1007/s00586-016-4745-4. Epub 2016 Sep 16.
16	Epigenetic silencing of HIC1 promotes epithelial-mesenchymal transition and drives progression in esophageal squamous cell carcinoma.Oncotarget. 2015 Nov 10;6(35):38151-65. doi: 10.18632/oncotarget.5832.
17	Inactivation of tumor suppressor gene HIC1 in gastric cancer is reversed via small activating RNAs.Gene. 2013 Sep 15;527(1):102-8. doi: 10.1016/j.gene.2013.05.034. Epub 2013 Jun 12.
18	P53 induction accompanying G2/M arrest upon knockdown of tumor suppressor HIC1 in U87MG glioma cells.Mol Cell Biochem. 2014 Oct;395(1-2):281-90. doi: 10.1007/s11010-014-2137-9. Epub 2014 Jul 4.
19	Loss of hypermethylated in cancer 1 (HIC1) promotes lung cancer progression.Cell Signal. 2019 Jan;53:162-169. doi: 10.1016/j.cellsig.2018.10.006. Epub 2018 Oct 10.
20	Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma.Genes Dev. 2008 Mar 15;22(6):770-85. doi: 10.1101/gad.1640908.
21	Hypermethylated in cancer 1(HIC1) suppresses non-small cell lung cancer progression by targeting interleukin-6/Stat3 pathway.Oncotarget. 2016 May 24;7(21):30350-64. doi: 10.18632/oncotarget.8734.
22	HIC1 loss promotes prostate cancer metastasis by triggering epithelial-mesenchymal transition.J Pathol. 2017 Aug;242(4):409-420. doi: 10.1002/path.4913. Epub 2017 Jun 13.
23	Assessment of DNA methylation for the detection of cervical neoplasia in liquid-based cytology specimens.Gynecol Oncol. 2010 Jan;116(1):99-104. doi: 10.1016/j.ygyno.2009.09.032.
24	Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
25	Hypermethylated in cancer 1 (HIC1), a tumor suppressor gene epigenetically deregulated in hyperparathyroid tumors by histone H3 lysine modification.J Clin Endocrinol Metab. 2012 Jul;97(7):E1307-15. doi: 10.1210/jc.2011-3136. Epub 2012 Apr 27.
26	Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.Nat Genet. 2019 Apr;51(4):606-610. doi: 10.1038/s41588-019-0351-9. Epub 2019 Feb 11.
27	Tissue-specific and mosaic imprinting defects underlie opposite congenital growth disorders in mice.PLoS Genet. 2018 Feb 22;14(2):e1007243. doi: 10.1371/journal.pgen.1007243. eCollection 2018 Feb.
28	Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis.Cancer Epidemiol Biomarkers Prev. 2009 Oct;18(10):2782-9. doi: 10.1158/1055-9965.EPI-09-0493. Epub 2009 Sep 15.
29	Promoter hypermethylation of RASSF1A, MGMT, and HIC-1 genes in benign and malignant colorectal tumors.Tumour Biol. 2011 Oct;32(5):845-52. doi: 10.1007/s13277-011-0156-7. Epub 2011 Jan 28.
30	Inactivation of the hypermethylated in cancer 1 tumour suppressor--not just a question of promoter hypermethylation?.Swiss Med Wkly. 2010 Nov 1;140:w13106. doi: 10.4414/smw.2010.13106. eCollection 2010.
31	HIC1 attenuates invasion and metastasis by inhibiting the IL-6/STAT3 signalling pathway in human pancreatic cancer.Cancer Lett. 2016 Jul 1;376(2):387-98. doi: 10.1016/j.canlet.2016.04.013. Epub 2016 Apr 13.
32	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.
33	Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
34	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.
35	The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
36	Additive effects of 5-aza-2'-deoxycytidine and irradiation on clonogenic survival of human medulloblastoma cell lines. Strahlenther Onkol. 2009 May;185(5):331-8. doi: 10.1007/s00066-009-1956-1. Epub 2009 May 15.
37	THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
38	Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011 Aug 15;187(4):1778-87. doi: 10.4049/jimmunol.1003919. Epub 2011 Jul 18.
39	Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way. Mol Nutr Food Res. 2017 Dec;61(12). doi: 10.1002/mnfr.201700260. Epub 2017 Nov 9.
40	Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
41	The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1. Mol Cancer Res. 2009 Jun;7(6):916-22. doi: 10.1158/1541-7786.MCR-08-0359. Epub 2009 Jun 2.
42	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
43	Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
44	Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
45	Bisphenol A stimulates the epithelial mesenchymal transition of estrogen negative breast cancer cells via FOXA1 signals. Arch Biochem Biophys. 2015 Nov 1;585:10-16. doi: 10.1016/j.abb.2015.09.006. Epub 2015 Sep 9.
46	Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
47	ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.