Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSIFTD8)

• DOT Name: LIM domain-containing protein 2 (LIMD2)
• Gene Name: LIMD2
• Related Disease:
  Advanced cancer
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland follicular carcinoma
  Thyroid gland papillary carcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Epithelial ovarian cancer
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Thyroid tumor
  Neoplasm
  Melanoma
• UniProt ID: LIMD2_HUMAN
• PDB ID: 2LZU
• Pfam ID: PF00412
• Sequence:
  MFQAAGAAQATPSHDAKGGGSSTVQRSKSFSLRAQVKETCAACQKTVYPMERLVADKLIF
  HNSCFCCKHCHTKLSLGSYAALHGEFYCKPHFQQLFKSKGNYDEGFGRKQHKELWAHKEV
  DPGTKTA
• Function: Acts as an activator of the protein-kinase ILK, thereby regulating cell motility.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Thyroid cancer	DIS3VLDH	Definitive	Biomarker	[2]
Thyroid gland carcinoma	DISMNGZ0	Definitive	Biomarker	[2]
Thyroid gland follicular carcinoma	DISFK2QT	Definitive	Altered Expression	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[6]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Melanoma	DIS1RRCY	Limited	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	LIM domain-containing protein 2 (LIMD2) increases the response to substance of Arsenic trioxide.	[18]

3 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 LIM domain-containing protein 2 (LIMD2).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of LIM domain-containing protein 2 (LIMD2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of LIM domain-containing protein 2 (LIMD2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of LIM domain-containing protein 2 (LIMD2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of LIM domain-containing protein 2 (LIMD2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of LIM domain-containing protein 2 (LIMD2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of LIM domain-containing protein 2 (LIMD2).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of LIM domain-containing protein 2 (LIMD2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of LIM domain-containing protein 2 (LIMD2).	[17]

References

• [1] LIMD2 Is Overexpressed in BRAF V600E-Positive Papillary Thyroid Carcinomas and Matched Lymph Node Metastases.Endocr Pathol. 2018 Sep;29(3):222-230. doi: 10.1007/s12022-018-9526-7.
• [2] LIMD2 targeted by miR?4a promotes the proliferation and invasion of nonsmall cell lung cancer cells.Mol Med Rep. 2018 Nov;18(5):4760-4766. doi: 10.3892/mmr.2018.9464. Epub 2018 Sep 6.
• [3] Epigenetic repression of PDZ-LIM domain-containing protein 2: implications for the biology and treatment of breast cancer.J Biol Chem. 2010 Apr 16;285(16):11786-92. doi: 10.1074/jbc.M109.086561. Epub 2010 Feb 25.
• [4] Expression profiling identifies genes that predict recurrence of breast cancer after adjuvant CMF-based chemotherapy.Breast Cancer Res Treat. 2009 Nov;118(1):45-56. doi: 10.1007/s10549-008-0207-y. Epub 2008 Oct 17.
• [5] DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target.Cancer Res. 2010 Mar 1;70(5):1766-72. doi: 10.1158/0008-5472.CAN-09-3263. Epub 2010 Feb 9.
• [6] Epigenetic repression of PDZ-LIM domain-containing protein 2 promotes ovarian cancer via NOS2-derived nitric oxide signaling.Oncotarget. 2016 Jan 12;7(2):1408-20. doi: 10.18632/oncotarget.6368.
• [7] Overexpression of LIMD2 promotes the progression of non-small cell lung cancer.Oncol Lett. 2019 Aug;18(2):2073-2081. doi: 10.3892/ol.2019.10473. Epub 2019 Jun 12.
• [8] LIMD2 is a small LIM-only protein overexpressed in metastatic lesions that regulates cell motility and tumor progression by directly binding to and activating the integrin-linked kinase.Cancer Res. 2014 Mar 1;74(5):1390-1403. doi: 10.1158/0008-5472.CAN-13-1275.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [15] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [16] 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.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.