Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7YLOFH)

• DOT Name: Ras association domain-containing protein 4 (RASSF4)
• Gene Name: RASSF4
• Related Disease:
  Lung cancer
  Lung carcinoma
  Malignant neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Nasopharyngeal carcinoma
  Plasma cell myeloma
  Advanced cancer
  Bone osteosarcoma
  Glioma
  Osteosarcoma
• UniProt ID: RASF4_HUMAN
• Pfam ID: PF16517 ; PF00788
• Sequence:
  MKEDCLPSSHVPISDSKSIQKSELLGLLKTYNCYHEGKSFQLRHREEEGTLIIEGLLNIA
  WGLRRPIRLQMQDDREQVHLPSTSWMPRRPSCPLKEPSPQNGNITAQGPSIQPVHKAESS
  TDSSGPLEEAEEAPQLMRTKSDASCMSQRRPKCRAPGEAQRIRRHRFSINGHFYNHKTSV
  FTPAYGSVTNVRVNSTMTTLQVLTLLLNKFRVEDGPSEFALYIVHESGERTKLKDCEYPL
  ISRILHGPCEKIARIFLMEADLGVEVPHEVAQYIKFEMPVLDSFVEKLKEEEEREIIKLT
  MKFQALRLTMLQRLEQLVEAK
• Function: Potential tumor suppressor. May act as a KRAS effector protein. May promote apoptosis and cell cycle arrest.
• Tissue Specificity: Widely expressed. Frequently down-regulated in tumor cell lines.
• KEGG Pathway: Hippo sig.ling pathway - multiple species (hsa04392)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Strong	Altered Expression	[1]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Malignant neoplasm	DISS6SNG	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[1]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[4]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[5]
Glioma	DIS5RPEH	Limited	Posttranslational Modification	[6]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[5]

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 Ras association domain-containing protein 4 (RASSF4).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ras association domain-containing protein 4 (RASSF4).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ras association domain-containing protein 4 (RASSF4).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras association domain-containing protein 4 (RASSF4).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ras association domain-containing protein 4 (RASSF4).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras association domain-containing protein 4 (RASSF4).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ras association domain-containing protein 4 (RASSF4).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras association domain-containing protein 4 (RASSF4).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras association domain-containing protein 4 (RASSF4).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Ras association domain-containing protein 4 (RASSF4).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ras association domain-containing protein 4 (RASSF4).	[16]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Ras association domain-containing protein 4 (RASSF4).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ras association domain-containing protein 4 (RASSF4).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ras association domain-containing protein 4 (RASSF4).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ras association domain-containing protein 4 (RASSF4).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ras association domain-containing protein 4 (RASSF4).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras association domain-containing protein 4 (RASSF4).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ras association domain-containing protein 4 (RASSF4).	[16]
Bilirubin	DMI0V4O	Investigative	Bilirubin increases the expression of Ras association domain-containing protein 4 (RASSF4).	[24]

References

• [1] RASSF4 is downregulated in nonsmall cell lung cancer and inhibits cancer cell proliferation and invasion.Tumour Biol. 2016 Apr;37(4):4865-71. doi: 10.1007/s13277-015-4343-9. Epub 2015 Nov 2.
• [2] RASSF4 is required for skeletal muscle differentiation.Cell Biol Int. 2020 Feb;44(2):381-390. doi: 10.1002/cbin.11238. Epub 2019 Sep 25.
• [3] Loss of RASSF4 Expression in Multiple Myeloma Promotes RAS-Driven Malignant Progression.Cancer Res. 2018 Mar 1;78(5):1155-1168. doi: 10.1158/0008-5472.CAN-17-1544. Epub 2017 Dec 19.
• [4] Aberrant methylation of RASSF4/AD037 in nasopharyngeal carcinoma.Oncol Rep. 2004 Oct;12(4):781-7.
• [5] RASSF4 Overexpression Inhibits the Proliferation, Invasion, EMT, and Wnt Signaling Pathway in Osteosarcoma Cells.Oncol Res. 2017 Jan 2;25(1):83-91. doi: 10.3727/096504016X14719078133447.
• [6] Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas.Oncogene. 2004 Mar 25;23(13):2408-19. doi: 10.1038/sj.onc.1207407.
• [7] 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.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [21] 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.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.