Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTYWMF6)

• DOT Name: Rhophilin-2 (RHPN2)
• Synonyms: 76 kDa RhoB effector protein; GTP-Rho-binding protein 2; p76RBE
• Gene Name: RHPN2
• Related Disease:
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal neoplasm
  Glioblastoma multiforme
  Glioma
  Malignant glioma
  Nasopharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
  Colorectal carcinoma
• UniProt ID: RHPN2_HUMAN
• PDB ID: 2VSV
• Pfam ID: PF03097 ; PF02185
• Sequence:
  MTDALLPAAPQPLEKENDGYFRKGCNPLAQTGRSKLQNQRAALNQQILKAVRMRTGAENL
  LKVATNSKVREQVRLELSFVNSDLQMLKEELEGLNISVGVYQNTEEAFTIPLIPLGLKET
  KDVDFAVVLKDFILEHYSEDGYLYEDEIADLMDLRQACRTPSRDEAGVELLMTYFIQLGF
  VESRFFPPTRQMGLLFTWYDSLTGVPVSQQNLLLEKASVLFNTGALYTQIGTRCDRQTQA
  GLESAIDAFQRAAGVLNYLKDTFTHTPSYDMSPAMLSVLVKMMLAQAQESVFEKISLPGI
  RNEFFMLVKVAQEAAKVGEVYQQLHAAMSQAPVKENIPYSWASLACVKAHHYAALAHYFT
  AILLIDHQVKPGTDLDHQEKCLSQLYDHMPEGLTPLATLKNDQQRRQLGKSHLRRAMAHH
  EESVREASLCKKLRSIEVLQKVLCAAQERSRLTYAQHQEEDDLLNLIDAPSVVAKTEQEV
  DIILPQFSKLTVTDFFQKLGPLSVFSANKRWTPPRSIRFTAEEGDLGFTLRGNAPVQVHF
  LDPYCSASVAGAREGDYIVSIQLVDCKWLTLSEVMKLLKSFGEDEIEMKVVSLLDSTSSM
  HNKSATYSVGMQKTYSMICLAIDDDDKTDKTKKISKKLSFLSWGTNKNRQKSASTLCLPS
  VGAARPQVKKKLPSPFSLLNSDSSWY
• Function: Binds specifically to GTP-Rho. May function in a Rho pathway to limit stress fiber formation and/or increase the turnover of F-actin structures in the absence of high levels of RhoA activity.
• Tissue Specificity: Widely expressed. Highly expressed in prostate, trachea, stomach, colon, thyroid and pancreas. Expressed at lower level in brain, spinal cord, kidney, placenta and liver.
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHO GTPases Activate Rhotekin and Rhophilins (R-HSA-5666185)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Genetic Variation	[1]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[1]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[2]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[1]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Malignant glioma	DISFXKOV	Strong	Biomarker	[3]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[1]

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 Rhophilin-2 (RHPN2).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Rhophilin-2 (RHPN2).	[18]

11 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 Rhophilin-2 (RHPN2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rhophilin-2 (RHPN2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rhophilin-2 (RHPN2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Rhophilin-2 (RHPN2).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Rhophilin-2 (RHPN2).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Rhophilin-2 (RHPN2).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Rhophilin-2 (RHPN2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rhophilin-2 (RHPN2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Rhophilin-2 (RHPN2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Rhophilin-2 (RHPN2).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Rhophilin-2 (RHPN2).	[17]

References

• [1] Novel Common Genetic Susceptibility Loci for Colorectal Cancer.J Natl Cancer Inst. 2019 Feb 1;111(2):146-157. doi: 10.1093/jnci/djy099.
• [2] Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019 Jan;51(1):76-87. doi: 10.1038/s41588-018-0286-6. Epub 2018 Dec 3.
• [3] RHPN2 drives mesenchymal transformation in malignant glioma by triggering RhoA activation.Cancer Res. 2013 Aug 15;73(16):5140-50. doi: 10.1158/0008-5472.CAN-13-1168-T. Epub 2013 Jun 17.
• [4] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [5] Human bone marrow mesenchymal stem cells-derived microRNA-205-containing exosomes impede the progression of prostate cancer through suppression of RHPN2.J Exp Clin Cancer Res. 2019 Dec 17;38(1):495. doi: 10.1186/s13046-019-1488-1.
• [6] 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.
• [7] 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.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.