Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1J9SEB)

• DOT Name: Rho-related GTP-binding protein RhoH (RHOH)
• Synonyms: GTP-binding protein TTF; Translocation three four protein
• Gene Name: RHOH
• Related Disease:
  Acute myelogenous leukaemia
  Neoplasm
  Advanced cancer
  B-cell neoplasm
  Classic Hodgkin lymphoma
  Colorectal carcinoma
  Epidermodysplasia verruciformis, susceptibility to, 4
  Exanthem
  Human papillomavirus infection
  Immunodeficiency
  Marginal zone lymphoma
  Non-hodgkin lymphoma
  Non-small-cell lung cancer
  Plasma cell myeloma
  Small lymphocytic lymphoma
  Epidermodysplasia verruciformis
  Small-cell lung cancer
  T-cell immunodeficiency with epidermodysplasia verruciformis
  Adult lymphoma
  B-cell lymphoma
  Follicular lymphoma
  Lymphoma
  Pediatric lymphoma
  Hairy cell leukaemia
  Osteoarthritis
  Squamous cell carcinoma
• UniProt ID: RHOH_HUMAN
• Pfam ID: PF00071
• Sequence:
  MLSSIKCVLVGDSAVGKTSLLVRFTSETFPEAYKPTVYENTGVDVFMDGIQISLGLWDTA
  GNDAFRSIRPLSYQQADVVLMCYSVANHNSFLNLKNKWIGEIRSNLPCTPVLVVATQTDQ
  REMGPHRASCVNAMEGKKLAQDVRAKGYLECSALSNRGVQQVFECAVRTAVNQARRRNRR
  RLFSINECKIF
• Function: Negative regulator of hematopoietic progenitor cell proliferation, survival and migration. Critical regulator of thymocyte development and T-cell antigen receptor (TCR) signaling by mediating recruitment and activation of ZAP70. Required for phosphorylation of CD3Z, membrane translocation of ZAP70 and subsequent activation of the ZAP70-mediated pathways. Essential for efficient beta-selection and positive selection by promoting the ZAP70-dependent phosphorylation of the LAT signalosome during pre-TCR and TCR signaling. Crucial for thymocyte maturation during DN3 to DN4 transition and during positive selection. Plays critical roles in mast cell function by facilitating phosphorylation of SYK in Fc epsilon RI-mediated signal transduction. Essential for the phosphorylation of LAT, LCP2, PLCG1 and PLCG2 and for Ca(2+) mobilization in mast cells. Binds GTP but lacks intrinsic GTPase activity and is resistant to Rho-specific GTPase-activating proteins. Inhibits the activation of NF-kappa-B by TNF and IKKB and the activation of CRK/p38 by TNF. Inhibits activities of RAC1, RHOA and CDC42. Negatively regulates leukotriene production in neutrophils.
• Tissue Specificity: Expressed only in hematopoietic cells. Present at very high levels in the thymus, less abundant in the spleen, and least abundant in the bone marrow. Expressed at a higher level in the TH1 subtype of T-helper cells than in the TH2 subpopulation. Expressed in neutrophils under inflammatory conditions, such as cystic fibrosis, ulcerative colitis and appendicitis.
• KEGG Pathway:
  Leukocyte transendothelial migration (hsa04670)
  Salmonella infection (hsa05132)
• Reactome Pathway: RHOH GTPase cycle (R-HSA-9013407)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Epidermodysplasia verruciformis, susceptibility to, 4	DISITX1P	Strong	Autosomal recessive	[7]
Exanthem	DISAFOQN	Strong	Biomarker	[8]
Human papillomavirus infection	DISX61LX	Strong	Biomarker	[9]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[10]
Marginal zone lymphoma	DISLZ4AO	Strong	Biomarker	[11]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[12]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[14]
Epidermodysplasia verruciformis	DIS54WBS	Moderate	Autosomal recessive	[15]
Small-cell lung cancer	DISK3LZD	moderate	Genetic Variation	[16]
T-cell immunodeficiency with epidermodysplasia verruciformis	DISPHUJV	Supportive	Autosomal recessive	[7]
Adult lymphoma	DISK8IZR	Disputed	Altered Expression	[17]
B-cell lymphoma	DISIH1YQ	Disputed	Biomarker	[11]
Follicular lymphoma	DISVEUR6	Disputed	Biomarker	[11]
Lymphoma	DISN6V4S	Disputed	Altered Expression	[17]
Pediatric lymphoma	DIS51BK2	Disputed	Altered Expression	[17]
Hairy cell leukaemia	DISTD2E5	Limited	Altered Expression	[1]
Osteoarthritis	DIS05URM	Limited	Biomarker	[18]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Rho-related GTP-binding protein RhoH (RHOH).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rho-related GTP-binding protein RhoH (RHOH).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Rho-related GTP-binding protein RhoH (RHOH).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Rho-related GTP-binding protein RhoH (RHOH).	[24]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Rho-related GTP-binding protein RhoH (RHOH).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Rho-related GTP-binding protein RhoH (RHOH).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho-related GTP-binding protein RhoH (RHOH).	[28]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Rho-related GTP-binding protein RhoH (RHOH).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rho-related GTP-binding protein RhoH (RHOH).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Rho-related GTP-binding protein RhoH (RHOH).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho-related GTP-binding protein RhoH (RHOH).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho-related GTP-binding protein RhoH (RHOH).	[30]

References

• [1] Repression of the RHOH gene by JunD.Biochem J. 2011 Jul 1;437(1):75-88. doi: 10.1042/BJ20100829.
• [2] Tissue-factor fusion proteins induce occlusion of tumor vessels.Thromb Res. 2010 Apr;125 Suppl 2:S143-50. doi: 10.1016/S0049-3848(10)70033-5.
• [3] Genomic structure and assignment of the RhoH/TTF small GTPase gene (ARHH) to 4p13 by in situ hybridization.Genomics. 1997 Jul 1;43(1):89-94. doi: 10.1006/geno.1997.4788.
• [4] Prognostic analysis of aberrant somatic hypermutation of RhoH gene in diffuse large B cell lymphoma.Leukemia. 2007 Aug;21(8):1846-7. doi: 10.1038/sj.leu.2404717. Epub 2007 Apr 19.
• [5] Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma.Blood. 2006 Aug 1;108(3):1013-20. doi: 10.1182/blood-2005-10-3949. Epub 2006 Apr 13.
• [6] 5-Fluorouracil as a Tumor-Treating Field-Sensitizer in Colon Cancer Therapy.Cancers (Basel). 2019 Dec 12;11(12):1999. doi: 10.3390/cancers11121999.
• [7] Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. J Clin Invest. 2012 Sep;122(9):3239-47. doi: 10.1172/JCI62949. Epub 2012 Aug 1.
• [8] EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104.Br J Cancer. 2013 Feb 5;108(2):469-76. doi: 10.1038/bjc.2012.495. Epub 2012 Nov 20.
• [9] Inherited MST1 deficiency underlies susceptibility to EV-HPV infections.PLoS One. 2012;7(8):e44010. doi: 10.1371/journal.pone.0044010. Epub 2012 Aug 27.
• [10] Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders.Exp Cell Res. 2013 Sep 10;319(15):2375-83. doi: 10.1016/j.yexcr.2013.07.002. Epub 2013 Jul 11.
• [11] Aberrant somatic hypermutations in thyroid lymphomas.Leuk Res. 2009 May;33(5):649-54. doi: 10.1016/j.leukres.2008.10.007. Epub 2008 Nov 18.
• [12] Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin's lymphoma and multiple myeloma.Oncogene. 2000 Apr 13;19(16):2023-32. doi: 10.1038/sj.onc.1203521.
• [13] Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer.Br J Cancer. 2019 Apr;120(9):903-912. doi: 10.1038/s41416-019-0444-3. Epub 2019 Apr 8.
• [14] Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation.Leukemia. 2006 Jun;20(6):1089-95. doi: 10.1038/sj.leu.2404183.
• [15] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [16] TTF-1- and/or CD56-positive Circulating Tumor Cells in patients with small cell lung cancer (SCLC).Sci Rep. 2017 Mar 28;7:45351. doi: 10.1038/srep45351.
• [17] Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis.Blood. 2005 Sep 1;106(5):1831-8. doi: 10.1182/blood-2004-10-3898. Epub 2005 May 24.
• [18] Multichromatic TTF staining characterizes cartilage matrix in osteoarthritis and bone development.Histol Histopathol. 2019 Mar;34(3):275-286. doi: 10.14670/HH-18-044. Epub 2018 Sep 20.
• [19] Unusual jaw metastasis from squamous cell lung cancer in heavy smoker: Two case reports and review of the literature.Medicine (Baltimore). 2017 May;96(21):e6987. doi: 10.1097/MD.0000000000006987.
• [20] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [21] 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.
• [22] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [23] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [24] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [25] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [26] 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.
• [27] 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.
• [28] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [29] DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer thapsigargin based on comparative gene expression profiling in Jurkat T cells. Toxicol Lett. 2014 Jan 30;224(3):395-406. doi: 10.1016/j.toxlet.2013.11.005. Epub 2013 Nov 15.
• [30] 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.
• [31] 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.