Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT25GVWY)

• DOT Name: Ras association domain-containing protein 6 (RASSF6)
• Gene Name: RASSF6
• Related Disease:
  Acute lymphocytic leukaemia
  Adenocarcinoma
  Breast cancer
  Breast carcinoma
  Childhood acute lymphoblastic leukemia
  Clear cell renal carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Leukemia
  Retinoblastoma
  Triple negative breast cancer
  Bladder cancer
  Chronic pancreatitis
  Gastric cancer
  Gonorrhea
  Hepatocellular carcinoma
  Matthew-Wood syndrome
  Melanoma
  Metastatic malignant neoplasm
  Metastatic melanoma
  Nasopharyngeal carcinoma
  Pancreatic ductal carcinoma
  Renal cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Bone osteosarcoma
  Osteosarcoma
  Neoplasm
  Neuroblastoma
• UniProt ID: RASF6_HUMAN
• Pfam ID: PF16517 ; PF00788
• Sequence:
  MLWEETGAAPAPARASDLPYRISSDHLKKEEKMTMMAHQYPSWIFINEKTFITREQLNSL
  LKTYNIFYENQKNLHILYGETEDGKLIVEGMLDIFWGVKRPIQLKIQDEKPFSSFTSMKS
  SDVFSSKGMTRWGEFDDLYRISELDRTQIPMSEKRNSQEDYLSYHSNTLKPHAKDEPDSP
  VLYRTMSEAALVRKRMKPLMMDRKERQKNRASINGHFYNHETSIFIPAFESETKVRVNSN
  MRTEEVIKQLLQKFKIENSPQDFALHIIFATGEQRRLKKTDIPLLQRLLQGPSEKNARIF
  LMDKDAEEISSDVAQYINFHFSLLESILQRLNEEEKREIQRIVTKFNKEKAIILKCLQNK
  LVIKTETTV
• Function: Involved in the induction of apoptosis, through both caspase-dependent and caspase-independent pathways. May act as a Ras effector protein. May suppress the serum-induced basal levels of NF-kappa-B.
• Tissue Specificity: Highest expression in thymus, kidney and placenta. Also detected in colon, small intestine and lung. Tends to be down-regulated in 30-60% of tumors derived from breast, colon, kidney liver, rectum, pancreas, stomach and the thyroid gland compared to the normal counterpart.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Leukemia	DISNAKFL	Strong	Altered Expression	[7]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[8]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[9]
Chronic pancreatitis	DISBUOMJ	moderate	Altered Expression	[10]
Gastric cancer	DISXGOUK	moderate	Biomarker	[11]
Gonorrhea	DISQ5AO6	moderate	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[12]
Matthew-Wood syndrome	DISA7HR7	moderate	Biomarker	[10]
Melanoma	DIS1RRCY	moderate	Biomarker	[13]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[5]
Metastatic melanoma	DISSL43L	moderate	Posttranslational Modification	[13]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[14]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[10]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[4]
Stomach cancer	DISKIJSX	moderate	Biomarker	[11]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[9]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[9]
Bone osteosarcoma	DIST1004	Disputed	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Disputed	Altered Expression	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[6]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[16]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ras association domain-containing protein 6 (RASSF6).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ras association domain-containing protein 6 (RASSF6).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ras association domain-containing protein 6 (RASSF6).	[22]

5 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 6 (RASSF6).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ras association domain-containing protein 6 (RASSF6).	[19]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Ras association domain-containing protein 6 (RASSF6).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras association domain-containing protein 6 (RASSF6).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras association domain-containing protein 6 (RASSF6).	[24]

References

• [1] Residual methylation of tumor suppressor gene promoters, RASSF6 and RASSF10, as novel biomarkers for minimal residual disease detection in adult acute lymphoblastic leukemia.Ann Hematol. 2019 Dec;98(12):2719-2727. doi: 10.1007/s00277-019-03775-y. Epub 2019 Sep 5.
• [2] Decreased level of RASSF6 in sporadic colorectal cancer and its anti-tumor effects both in vitro and in vivo.Oncotarget. 2016 Apr 12;7(15):19813-23. doi: 10.18632/oncotarget.7852.
• [3] Downregulation of RASSF6 promotes breast cancer growth and chemoresistance through regulation of Hippo signaling.Biochem Biophys Res Commun. 2018 Sep 18;503(4):2340-2347. doi: 10.1016/j.bbrc.2018.06.159. Epub 2018 Jul 2.
• [4] RASSF6-mediated inhibition of Mcl-1 through JNK activation improves the anti-tumor effects of sorafenib in renal cell carcinoma.Cancer Lett. 2018 Sep 28;432:75-83. doi: 10.1016/j.canlet.2018.05.048. Epub 2018 Jun 1.
• [5] MiR-496 promotes migration and epithelial-mesenchymal transition by targeting RASSF6 in colorectal cancer.J Cell Physiol. 2020 Feb;235(2):1469-1479. doi: 10.1002/jcp.29066. Epub 2019 Jul 4.
• [6] RASSF6-TRIM16 axis promotes cell proliferation, migration and invasion in esophageal squamous cell carcinoma.J Genet Genomics. 2019 Oct 20;46(10):477-488. doi: 10.1016/j.jgg.2019.10.004. Epub 2019 Nov 14.
• [7] The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias.Mol Cancer. 2009 Jul 1;8:42. doi: 10.1186/1476-4598-8-42.
• [8] The RASSF6 Tumor Suppressor Protein Regulates Apoptosis and Cell Cycle Progression via Retinoblastoma Protein.Mol Cell Biol. 2018 Aug 15;38(17):e00046-18. doi: 10.1128/MCB.00046-18. Print 2018 Sep 1.
• [9] RASSF6 Is Downregulated In Human Bladder Cancers And Regulates Doxorubicin Sensitivity And Mitochondrial Membrane Potential Via The Hippo Signaling Pathway.Onco Targets Ther. 2019 Nov 5;12:9189-9200. doi: 10.2147/OTT.S217041. eCollection 2019.
• [10] Low RASSF6 expression in pancreatic ductal adenocarcinoma is associated with poor survival.World J Gastroenterol. 2015 Jun 7;21(21):6621-30. doi: 10.3748/wjg.v21.i21.6621.
• [11] miR-181a-5p promotes the progression of gastric cancer via RASSF6-mediated MAPK signalling activation.Cancer Lett. 2017 Mar 28;389:11-22. doi: 10.1016/j.canlet.2016.12.033. Epub 2016 Dec 30.
• [12] Overexpression of RAS-Association Domain Family 6 (RASSF6) Inhibits Proliferation and Tumorigenesis in Hepatocellular Carcinoma Cells.Oncol Res. 2017 Jul 5;25(6):1001-1008. doi: 10.3727/096504016X14796039599926. Epub 2016 Nov 24.
• [13] RASSF6 exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cells.Epigenetics. 2014 Nov;9(11):1496-503. doi: 10.4161/15592294.2014.983361.
• [14] Downregulation of Ras association domain family member 6 (RASSF6) underlies the treatment resistance of highly metastatic nasopharyngeal carcinoma cells.PLoS One. 2014 Jul 16;9(7):e100843. doi: 10.1371/journal.pone.0100843. eCollection 2014.
• [15] Downregulation of lncRNA CASC2 facilitates osteosarcoma growth and invasion through miR-181a.Cell Prolif. 2018 Feb;51(1):e12409. doi: 10.1111/cpr.12409. Epub 2017 Nov 30.
• [16] The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma.Mol Cancer. 2012 Jun 13;11:40. doi: 10.1186/1476-4598-11-40.
• [17] 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.
• [18] 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.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] 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.
• [21] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [22] 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.
• [23] Low dose of bisphenol a modulates ovarian cancer gene expression profile and promotes epithelial to mesenchymal transition via canonical Wnt pathway. Toxicol Sci. 2018 Aug 1;164(2):527-538.
• [24] 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.