Details of Drug Off-Target (DOT)

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

• DOT Name: ATP-dependent RNA helicase DHX33 (DHX33)
• Synonyms: EC 3.6.4.13; DEAH box protein 33
• Gene Name: DHX33
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Advanced cancer
  Hepatocellular carcinoma
  Lymphoma, non-Hodgkin, familial
  Neoplasm
  Non-hodgkin lymphoma
  Lung cancer
  Lung carcinoma
• UniProt ID: DHX33_HUMAN
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF21010 ; PF04408 ; PF00271 ; PF07717
• Sequence:
  MPEEAGFPPAKRFRPGSGPPSRAGSFPPGRQVVMLLTAGSGGRGGGGGRRQQPPLAQPSA
  SPYPEAVELQRRSLPIFQARGQLLAQLRNLDNAVLIGETGSGKTTQIPQYLYEGGISRQG
  IIAVTQPRRVAAISLATRVSDEKRTELGKLVGYTVRFDDVTSEDTRIKFLTDGMLLREAI
  SDSLLRKYSCVILDEAHERTIHTDVLFGVVKAAQKRRKELGKLPLKVIVMSATMDVDLFS
  QYFNGAPVLYLEGRQHPIQVFYTKQPQNDYLHAALVSVFQIHQEAPSSQDILVFLTGQEE
  IEAMSKTCRDIAKHLPDGCPAMLVLPLYASLPYAQQLRVFQGAPKGYRKVIISTNIAETS
  ITITGIKYVVDTGMVKAKKYNPDSGLEVLAVQRVSKTQAWQRTGRAGREDSGICYRLYTE
  DEFEKFDKMTVPEIQRCNLASVMLQLLAMKVPNVLTFDFMSKPSPDHIQAAIAQLDLLGA
  LEHKDDQLTLTPMGRKMAAFPLEPKFAKTILMSPKFHCTEEILTIVSLLSVDSVLHNPPS
  RREEVQGVRKKFISSEGDHMTLLNIYRTFKNLGGNKDWCKENFVNSKNMTLVAEVRAQLR
  DICLKMSMPIASSRGDVESVRRCLAHSLFMSTAELQPDGTYATTDTHQPVAIHPSSVLFH
  CKPACVVYTELLYTNKCYMRDLCVIDAQWLYEAAPEYFRRKLRTARN
• Function: Implicated in nucleolar organization, ribosome biogenesis, protein synthesis and cytoplasmic dsRNA sensing. Stimulates RNA polymerase I transcription of the 47S precursor rRNA. Associates with ribosomal DNA (rDNA) loci where it is involved in POLR1A recruitment. In the cytoplasm, promotes elongation-competent 80S ribosome assembly at the late stage of mRNA translation initiation. Senses cytosolic dsRNA mediating NLRP3 inflammasome formation in macrophages and type I interferon production in myeloid dendritic cells. Required for NLRP3 activation induced by viral dsRNA and bacterial RNA. In dendritic cells, required for induction of type I interferon production induced by cytoplasmic dsRNA via the activation of MAPK and NF-kappa-B signaling pathways.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Altered Expression	[4]
Lung cancer	DISCM4YA	Limited	Altered Expression	[5]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[5]

10 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 ATP-dependent RNA helicase DHX33 (DHX33).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP-dependent RNA helicase DHX33 (DHX33).	[15]

References

• [1] The RNA helicase DHX33 is required for cancer cell proliferation in human glioblastoma and confers resistance to PI3K/mTOR inhibition.Cell Signal. 2019 Feb;54:170-178. doi: 10.1016/j.cellsig.2018.12.005. Epub 2018 Dec 12.
• [2] Recombinant DHX33 Protein Possesses Dual DNA/RNA Helicase Activity.Biochemistry. 2019 Jan 29;58(4):250-258. doi: 10.1021/acs.biochem.8b00166. Epub 2018 Jun 13.
• [3] DHX33 expression is increased in hepatocellular carcinoma and indicates poor prognosis.Biochem Biophys Res Commun. 2016 May 13;473(4):1163-1169. doi: 10.1016/j.bbrc.2016.04.033. Epub 2016 Apr 9.
• [4] Role of DHX33 in c-Myc-induced cancers.Carcinogenesis. 2017 Jun 1;38(6):649-660. doi: 10.1093/carcin/bgx041.
• [5] DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle.Mol Cell Biol. 2016 Nov 14;36(23):2903-2917. doi: 10.1128/MCB.00314-16. Print 2016 Dec 1.
• [6] 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.
• [7] 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.
• [8] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.