Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL5J132)

• DOT Name: Rhomboid-related protein 4 (RHBDD1)
• Synonyms: RRP4; EC 3.4.21.105; Rhomboid domain-containing protein 1; Rhomboid-like protein 4
• Gene Name: RHBDD1
• Related Disease:
  Adult glioblastoma
  Alzheimer disease
  Brain cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Neoplasm
  Advanced cancer
  Colonic neoplasm
  Metastatic malignant neoplasm
• UniProt ID: RHBL4_HUMAN
• PDB ID: 5EPP
• EC Number: 3.4.21.105
• Pfam ID: PF01694
• Sequence:
  MQRRSRGINTGLILLLSQIFHVGINNIPPVTLATLALNIWFFLNPQKPLYSSCLSVEKCY
  QQKDWQRLLLSPLHHADDWHLYFNMASMLWKGINLERRLGSRWFAYVITAFSVLTGVVYL
  LLQFAVAEFMDEPDFKRSCAVGFSGVLFALKVLNNHYCPGGFVNILGFPVPNRFACWVEL
  VAIHLFSPGTSFAGHLAGILVGLMYTQGPLKKIMEACAGGFSSSVGYPGRQYYFNSSGSS
  GYQDYYPHGRPDHYEEAPRNYDTYTAGLSEEEQLERALQASLWDRGNTRNSPPPYGFHLS
  PEEMRRQRLHRFDSQ
• Function: Intramembrane-cleaving serine protease that cleaves single transmembrane or multi-pass membrane proteins in the hydrophobic plane of the membrane, luminal loops and juxtamembrane regions. Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors. Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded membrane proteins. Required for the degradation process of some specific misfolded endoplasmic reticulum (ER) luminal proteins. Participates in the transfer of misfolded proteins from the ER to the cytosol, where they are destroyed by the proteasome in a ubiquitin-dependent manner. Functions in BIK, MPZ, PKD1, PTCRA, RHO, STEAP3 and TRAC processing. Involved in the regulation of exosomal secretion; inhibits the TSAP6-mediated secretion pathway. Involved in the regulation of apoptosis; modulates BIK-mediated apoptotic activity. Also plays a role in the regulation of spermatogenesis; inhibits apoptotic activity in spermatogonia.
• Tissue Specificity: Expressed strongly in testis.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Brain cancer	DISBKFB7	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[8]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[8]

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 Rhomboid-related protein 4 (RHBDD1).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rhomboid-related protein 4 (RHBDD1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Rhomboid-related protein 4 (RHBDD1).	[19]

8 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 Rhomboid-related protein 4 (RHBDD1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Rhomboid-related protein 4 (RHBDD1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rhomboid-related protein 4 (RHBDD1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Rhomboid-related protein 4 (RHBDD1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Rhomboid-related protein 4 (RHBDD1).	[15]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Rhomboid-related protein 4 (RHBDD1).	[16]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Rhomboid-related protein 4 (RHBDD1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rhomboid-related protein 4 (RHBDD1).	[18]

References

• [1] Lentiviral vector mediated delivery of RHBDD1 shRNA down regulated the proliferation of human glioblastoma cells.Technol Cancer Res Treat. 2014 Feb;13(1):87-93. doi: 10.7785/tcrt.2012.500362. Epub 2013 Jul 23.
• [2] Emerging Alternative Proteinases in APP Metabolism and Alzheimer's Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP.Front Aging Neurosci. 2019 Sep 24;11:244. doi: 10.3389/fnagi.2019.00244. eCollection 2019.
• [3] MicroRNA-138-5p inhibits cell migration, invasion and EMT in breast cancer by directly targeting RHBDD1.Breast Cancer. 2019 Nov;26(6):817-825. doi: 10.1007/s12282-019-00989-w. Epub 2019 Jun 26.
• [4] miR-145-5p restrained cell growth, invasion, migration and tumorigenesis via modulating RHBDD1 in colorectal cancer via the EGFR-associated signaling pathway.Int J Biochem Cell Biol. 2019 Dec;117:105641. doi: 10.1016/j.biocel.2019.105641. Epub 2019 Nov 3.
• [5] Lentivirus-mediated silencing of rhomboid domain containing 1 suppresses tumor growth and induces apoptosis in hepatoma HepG2 cells.Asian Pac J Cancer Prev. 2013;14(1):5-9. doi: 10.7314/apjcp.2013.14.1.5.
• [6] Clonal analyses of refractory testicular germ cell tumors.PLoS One. 2019 Mar 14;14(3):e0213815. doi: 10.1371/journal.pone.0213815. eCollection 2019.
• [7] Lentivirus-mediated knockdown of rhomboid domain containing 1 inhibits colorectal cancer cell growth.Mol Med Rep. 2015 Jul;12(1):377-81. doi: 10.3892/mmr.2015.3365. Epub 2015 Feb 17.
• [8] RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1.J Exp Clin Cancer Res. 2018 Feb 9;37(1):22. doi: 10.1186/s13046-018-0687-5.
• [9] 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.
• [10] 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.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] 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.
• [16] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [17] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] 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.