Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXKGIB3)

• DOT Name: Ras association domain-containing protein 8 (RASSF8)
• Synonyms: Carcinoma-associated protein HOJ-1
• Gene Name: RASSF8
• Related Disease:
  Breast cancer
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Cutaneous melanoma
  Melanoma
  Small-cell lung cancer
  Gastric cancer
  Stomach cancer
• UniProt ID: RASF8_HUMAN
• PDB ID: 2CS4
• Pfam ID: PF21712
• Sequence:
  MELKVWVDGVQRIVCGVTEVTTCQEVVIALAQAIGRTGRYTLIEKWRDTERHLAPHENPI
  ISLNKWGQYASDVQLILRRTGPSLSERPTSDSVARIPERTLYRQSLPPLAKLRPQIDKSI
  KRREPKRKSLTFTGGAKGLMDIFGKGKETEFKQKVLNNCKTTADELKKLIRLQTEKLQSI
  EKQLESNEIEIRFWEQKYNSNLEEEIVRLEQKIKRNDVEIEEEEFWENELQIEQENEKQL
  KDQLQEIRQKITECENKLKDYLAQIRTMESGLEAEKLQREVQEAQVNEEEVKGKIGKVKG
  EIDIQGQQSLRLENGIKAVERSLGQATKRLQDKEQELEQLTKELRQVNLQQFIQQTGTKV
  TVLPAEPIEIEASHADIEREAPFQSGSLKRPGSSRQLPSNLRILQNPISSGFNPEGIYV
• Tissue Specificity: Widely expressed as a 6.2 kb transcript. A 2.2 kb alternatively spliced transcript is expressed exclusively in testis.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Lung neoplasm	DISVARNB	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Cutaneous melanoma	DIS3MMH9	moderate	Biomarker	[7]
Melanoma	DIS1RRCY	moderate	Biomarker	[7]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[8]
Gastric cancer	DISXGOUK	Limited	Biomarker	[9]
Stomach cancer	DISKIJSX	Limited	Biomarker	[9]

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 Ras association domain-containing protein 8 (RASSF8).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ras association domain-containing protein 8 (RASSF8).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Ras association domain-containing protein 8 (RASSF8).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras association domain-containing protein 8 (RASSF8).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras association domain-containing protein 8 (RASSF8).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras association domain-containing protein 8 (RASSF8).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras association domain-containing protein 8 (RASSF8).	[14]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Ras association domain-containing protein 8 (RASSF8).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ras association domain-containing protein 8 (RASSF8).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ras association domain-containing protein 8 (RASSF8).	[17]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Ras association domain-containing protein 8 (RASSF8).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras association domain-containing protein 8 (RASSF8).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras association domain-containing protein 8 (RASSF8).	[21]

References

• [1] E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases.J Biol Chem. 2018 Apr 13;293(15):5624-5635. doi: 10.1074/jbc.RA117.000623. Epub 2018 Feb 21.
• [2] Over-Expressed miR-224 Promotes the Progression of Cervical Cancer via Targeting RASSF8.PLoS One. 2016 Sep 14;11(9):e0162378. doi: 10.1371/journal.pone.0162378. eCollection 2016.
• [3] MiR-505 mediates methotrexate resistance in colorectal cancer by targeting RASSF8.J Pharm Pharmacol. 2018 Jul;70(7):937-951. doi: 10.1111/jphp.12913. Epub 2018 May 3.
• [4] RASSF8 downregulation promotes lymphangiogenesis and metastasis in esophageal squamous cell carcinoma.Oncotarget. 2015 Oct 27;6(33):34510-24. doi: 10.18632/oncotarget.5923.
• [5] Identification of RASSF8 as a candidate lung tumor suppressor gene.Oncogene. 2006 Jun 29;25(28):3934-8. doi: 10.1038/sj.onc.1209422. Epub 2006 Feb 6.
• [6] The circRNA circPTPRA suppresses epithelial-mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p.EBioMedicine. 2019 Jun;44:182-193. doi: 10.1016/j.ebiom.2019.05.032. Epub 2019 May 31.
• [7] RASSF8 regulates progression of cutaneous melanoma through nuclear factor-b.Oncotarget. 2015 Oct 6;6(30):30165-77. doi: 10.18632/oncotarget.5030.
• [8] Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.Nat Genet. 2012 Oct;44(10):1111-6. doi: 10.1038/ng.2405. Epub 2012 Sep 2.
• [9] The regulation and function of microRNA-377/RASSF8 signaling axis in gastric cancer.Oncol Lett. 2018 Mar;15(3):3630-3638. doi: 10.3892/ol.2018.7740. Epub 2018 Jan 8.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [16] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [17] 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.
• [18] 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.
• [19] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [20] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [21] 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.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.