Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0VVG4V)

• DOT Name: Inhibitor of growth protein 4 (ING4)
• Synonyms: p29ING4
• Gene Name: ING4
• Related Disease:
  Lung adenocarcinoma
  Adenocarcinoma
  Advanced cancer
  Astrocytoma
  Bladder cancer
  Bone osteosarcoma
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Diabetic retinopathy
  Epithelial ovarian cancer
  Gastric cancer
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate neoplasm
  Pulmonary fibrosis
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Gastric adenocarcinoma
  Head and neck cancer
  Head and neck carcinoma
  Metastatic malignant neoplasm
  Stomach cancer
  Adult glioblastoma
  Glioblastoma multiforme
  Melanoma
  Nasopharyngeal carcinoma
  Non-small-cell lung cancer
  Pancreatic cancer
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Small lymphocytic lymphoma
• UniProt ID: ING4_HUMAN
• PDB ID: 2K1J; 2M1R; 2PNX; 2VNF; 4AFL
• Pfam ID: PF12998
• Sequence:
  MAAGMYLEHYLDSIENLPFELQRNFQLMRDLDQRTEDLKAEIDKLATEYMSSARSLSSEE
  KLALLKQIQEAYGKCKEFGDDKVQLAMQTYEMVDKHIRRLDTDLARFEADLKEKQIESSD
  YDSSSSKGKKKGRTQKEKKAARARSKGKNSDEEAPKTAQKKLKLVRTSPEYGMPSVTFGS
  VHPSDVLDMPVDPNEPTYCLCHQVSYGEMIGCDNPDCSIEWFHFACVGLTTKPRGKWFCP
  RCSQERKKK
• Function: Component of HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), and have reduced activity toward histone H4. Through chromatin acetylation it may function in DNA replication. May inhibit tumor progression by modulating the transcriptional output of signaling pathways which regulate cell proliferation. Can suppress brain tumor angiogenesis through transcriptional repression of RELA/NFKB3 target genes when complexed with RELA. May also specifically suppress loss of contact inhibition elicited by activated oncogenes such as MYC. Represses hypoxia inducible factor's (HIF) activity by interacting with HIF prolyl hydroxylase 2 (EGLN1). Can enhance apoptosis induced by serum starvation in mammary epithelial cell line HC11.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Astrocytoma	DISL3V18	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[11]
Colorectal neoplasm	DISR1UCN	Strong	Therapeutic	[12]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[14]
Gastric cancer	DISXGOUK	Strong	Biomarker	[15]
Glioma	DIS5RPEH	Strong	Biomarker	[16]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[18]
Lung carcinoma	DISTR26C	Strong	Biomarker	[18]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[14]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[14]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[19]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[20]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[21]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Cervical cancer	DISFSHPF	moderate	Altered Expression	[22]
Cervical carcinoma	DIST4S00	moderate	Altered Expression	[22]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[23]
Gastric adenocarcinoma	DISWWLTC	moderate	Biomarker	[24]
Head and neck cancer	DISBPSQZ	moderate	Biomarker	[25]
Head and neck carcinoma	DISOU1DS	moderate	Biomarker	[25]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[22]
Stomach cancer	DISKIJSX	moderate	Biomarker	[15]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[26]
Glioblastoma multiforme	DISK8246	Disputed	Altered Expression	[26]
Melanoma	DIS1RRCY	Disputed	Biomarker	[27]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[28]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[29]
Pancreatic cancer	DISJC981	Limited	Biomarker	[30]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[31]
Prostate cancer	DISF190Y	Limited	Biomarker	[32]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[32]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[23]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Inhibitor of growth protein 4 (ING4).	[34]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inhibitor of growth protein 4 (ING4).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inhibitor of growth protein 4 (ING4).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Inhibitor of growth protein 4 (ING4).	[37]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Inhibitor of growth protein 4 (ING4).	[38]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Inhibitor of growth protein 4 (ING4).	[39]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Inhibitor of growth protein 4 (ING4).	[40]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Inhibitor of growth protein 4 (ING4).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Inhibitor of growth protein 4 (ING4).	[42]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Inhibitor of growth protein 4 (ING4).	[43]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Inhibitor of growth protein 4 (ING4).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Inhibitor of growth protein 4 (ING4).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Inhibitor of growth protein 4 (ING4).	[46]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Inhibitor of growth protein 4 (ING4).	[47]

References

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• [2] ING4 induces cell growth inhibition in human lung adenocarcinoma A549 cells by means of Wnt-1/beta-catenin signaling pathway. Anat Rec (Hoboken). 2008 May;291(5):593-600.
• [3] ING4 suppresses hepatocellular carcinoma via a NF-B/miR-155/FOXO3a signaling axis.Int J Biol Sci. 2019 Jan 1;15(2):369-385. doi: 10.7150/ijbs.28422. eCollection 2019.
• [4] Loss of inhibitor of growth (ING-4) is implicated in the pathogenesis and progression of human astrocytomas.Brain Pathol. 2010 Mar;20(2):490-7. doi: 10.1111/j.1750-3639.2009.00325.x. Epub 2009 Aug 6.
• [5] Reduced ING4 Expression Is Associated with the Malignancy of Human Bladder.Urol Int. 2015;94(4):464-71. doi: 10.1159/000364832. Epub 2015 Mar 14.
• [6] Adenovirus-mediated ING4 Gene Transfer in Osteosarcoma Suppresses Tumor Growth via Induction of Apoptosis and Inhibition of Tumor Angiogenesis.Technol Cancer Res Treat. 2015 Aug;14(4):369-78. doi: 10.1177/1533034614500424. Epub 2014 Oct 16.
• [7] The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis.Nature. 2004 Mar 18;428(6980):328-32. doi: 10.1038/nature02329.
• [8] Differential cellular localization of CELSR2 and ING4 and correlations with hormone receptor status in breast cancer.Histol Histopathol. 2018 Aug;33(8):835-842. doi: 10.14670/HH-11-979. Epub 2018 Feb 28.
• [9] Oncogenic microRNA-765 promotes the growth and metastasis of breast carcinoma by directly targeting ING4.J Cell Biochem. 2020 Aug;121(8-9):3887-3900. doi: 10.1002/jcb.29545. Epub 2019 Nov 13.
• [10] ING4 is negatively correlated with microvessel density in colon cancer.Tumour Biol. 2012 Dec;33(6):2357-64. doi: 10.1007/s13277-012-0498-9. Epub 2012 Sep 28.
• [11] Long non-coding RNA FENDRR restrains the aggressiveness of CRC via regulating miR-18a-5p/ING4 axis.J Cell Biochem. 2020 Aug;121(8-9):3973-3985. doi: 10.1002/jcb.29555. Epub 2019 Nov 13.
• [12] ING4 suppresses tumor angiogenesis and functions as a prognostic marker in human colorectal cancer.Oncotarget. 2016 Nov 29;7(48):79017-79031. doi: 10.18632/oncotarget.12984.
• [13] Inhibitor of growth 4 affects hypoxia-induced migration and angiogenesis regulation in retinal pigment epithelial cells.J Cell Physiol. 2019 Sep;234(9):15243-15256. doi: 10.1002/jcp.28170. Epub 2019 Jan 22.
• [14] Combinatorial strategies based on CRAd-IL24 and CRAd-ING4 virotherapy with anti-angiogenesis treatment for ovarian cancer.J Ovarian Res. 2016 Jun 27;9(1):38. doi: 10.1186/s13048-016-0248-5.
• [15] N-methyl-N-nitro-N-nitrosoguanidine-mediated ING4 downregulation contributed to the angiogenesis of transformed human gastric epithelial cells.Life Sci. 2018 Apr 15;199:179-187. doi: 10.1016/j.lfs.2018.02.034. Epub 2018 Feb 26.
• [16] Synergistic antitumor effect of ING4/PTEN double tumor suppressors mediated by adenovirus modified with arginine-glycine-aspartate on glioma.J Neurosurg Sci. 2020 Apr;64(2):173-180. doi: 10.23736/S0390-5616.17.03978-9. Epub 2017 Apr 12.
• [17] Downregulation and translocation of nuclear ING4 is correlated with tumorigenesis and progression of head and neck squamous cell carcinoma.Oral Oncol. 2011 Mar;47(3):217-23. doi: 10.1016/j.oraloncology.2011.01.004.
• [18] MicroRNA?14 upregulates HIF? and VEGF by targeting ING4 in lung cancer cells.Mol Med Rep. 2019 Jun;19(6):4935-4945. doi: 10.3892/mmr.2019.10170. Epub 2019 Apr 16.
• [19] Miz1, a Novel Target of ING4, Can Drive Prostate Luminal Epithelial Cell Differentiation.Prostate. 2017 Jan;77(1):49-59. doi: 10.1002/pros.23249. Epub 2016 Aug 16.
• [20] Expression of HIF-1A/VEGF/ING-4 Axis in Pulmonary Sarcoidosis.Adv Exp Med Biol. 2015;866:61-9. doi: 10.1007/5584_2015_144.
• [21] Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas.Gene. 2005 Aug 15;356:109-17. doi: 10.1016/j.gene.2005.02.014.
• [22] The expression of inhibitor of growth 4 is reduced in cervical cancer tissues.Eur Rev Med Pharmacol Sci. 2016 Jul;20(15):3178-85.
• [23] Inhibitor of growth 4 inhibits cell proliferation, migration, and induces apoptosis of renal cell carcinoma cells.J Cell Biochem. 2019 Apr;120(4):6709-6717. doi: 10.1002/jcb.27967. Epub 2018 Nov 2.
• [24] Down-regulation of ING4 is associated with initiation and progression of lung cancer.Histopathology. 2010 Aug;57(2):271-81. doi: 10.1111/j.1365-2559.2010.03623.x.
• [25] Tumor-specific mutation and downregulation of ING5 detected in oral squamous cell carcinoma.Int J Cancer. 2010 Nov 1;127(9):2088-94. doi: 10.1002/ijc.25224.
• [26] Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1.Cancer Res. 2007 Mar 15;67(6):2552-8. doi: 10.1158/0008-5472.CAN-06-3870.
• [27] Role of inhibitor of growth 4 in the suppression of human melanoma cells through the Fas/FasL-mediated apoptosis pathway.Int J Mol Med. 2018 Feb;41(2):1055-1061. doi: 10.3892/ijmm.2017.3274. Epub 2017 Nov 20.
• [28] Adenovirus-mediated co-expression of ING4 and PTEN cooperatively enhances their antitumor activity in human hepatocellular carcinoma cells.Acta Biochim Biophys Sin (Shanghai). 2016 Aug;48(8):704-13. doi: 10.1093/abbs/gmw062. Epub 2016 Jul 14.
• [29] miR-650 promotes non-small cell lung cancer cell proliferation and invasion by targeting ING4 through Wnt-1/-catenin pathway.Oncol Lett. 2019 Nov;18(5):4621-4628. doi: 10.3892/ol.2019.10805. Epub 2019 Sep 4.
• [30] Synergistic antitumor effect of adenovirus-mediated hING4 gene therapy and (125)I radiation therapy on pancreatic cancer.Cancer Lett. 2012 Mar 28;316(2):211-8. doi: 10.1016/j.canlet.2011.11.003. Epub 2011 Nov 7.
• [31] The inhibitor of growth 1 (ING1) proteins suppress angiogenesis and differentially regulate angiopoietin expression in glioblastoma cells.Oncol Res. 2009;18(2-3):95-105. doi: 10.3727/096504009789954645.
• [32] Identification of the inhibitor of growth protein 4 (ING4) as a potential target in prostate cancer therapy.Mol Cell Biochem. 2020 Jan;464(1-2):153-167. doi: 10.1007/s11010-019-03657-x. Epub 2019 Nov 27.
• [33] Cytokinesis arrest and multiple centrosomes in B cell chronic lymphocytic leukaemia.J Cell Mol Med. 2018 May;22(5):2846-2855. doi: 10.1111/jcmm.13579. Epub 2018 Mar 7.
• [34] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
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• [36] 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.
• [37] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [38] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [39] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
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• [43] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [44] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [45] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [46] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [47] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.