Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRA3265)

• DOT Name: PR domain zinc finger protein 8 (PRDM8)
• Synonyms: EC 2.1.1.-; PR domain-containing protein 8
• Gene Name: PRDM8
• Related Disease:
  Rheumatoid arthritis
  Anaplastic large cell lymphoma
  Bone marrow failure syndrome
  Dyskeratosis congenita
  Early-onset Lafora body disease
  Neoplasm
  Advanced cancer
  Hepatocellular carcinoma
• UniProt ID: PRDM8_HUMAN
• EC Number: 2.1.1.-
• Pfam ID: PF21549 ; PF13894
• Sequence:
  MEDTGIQRGIWDGDAKAVQQCLTDIFTSVYTTCDIPENAIFGPCVLSHTSLYDSIAFIAL
  KSTDKRTVPYIFRVDTSAANGSSEGLMWLRLVQSARDKEEQNLEAYIKNGQLFYRSLRRI
  AKDEELLVWYGKELTELLLLCPSRSHNKMNGSSPYTCLECSQRFQFEFPYVAHLRFRCPK
  RLHSADISPQDEQGGGVGTKDHGGGGGGGKDQQQQQQEAPLGPGPKFCKAGPLHHYPSPS
  PESSNPSAAAGGSSAKPSTDFHNLARELENSRGGSSCSPAQSLSSGSGSGGGGGHQEAEL
  SPDGIATGGGKGKRKFPEEAAEGGGGAGLVGGRGRFVERPLPASKEDLVCTPQQYRASGS
  YFGLEENGRLFAPPSPETGEAKRSAFVEVKKAARAASLQEEGTADGAGVASEDQDAGGGG
  GSSTPAAASPVGAEKLLAPRPGGPLPSRLEGGSPARGSAFTSVPQLGSAGSTSGGGGTGA
  GAAGGAGGGQGAASDERKSAFSQPARSFSQLSPLVLGQKLGALEPCHPADGVGPTRLYPA
  AADPLAVKLQGAADLNGGCGSLPSGGGGLPKQSPFLYATAFWPKSSAAAAAAAAAAAAGP
  LQLQLPSALTLLPPSFTSLCLPAQNWCAKCNASFRMTSDLVYHMRSHHKKEYAMEPLVKR
  RREEKLKCPICNESFRERHHLSRHMTSHN
• Function: Probable histone methyltransferase, preferentially acting on 'Lys-9' of histone H3. Involved in the control of steroidogenesis through transcriptional repression of steroidogenesis marker genes such as CYP17A1 and LHCGR. Forms with BHLHE22 a transcriptional repressor complex controlling genes involved in neural development and neuronal differentiation. In the retina, it is required for rod bipolar and type 2 OFF-cone bipolar cell survival.
• Tissue Specificity: Expressed in brain, heart, skeletal muscle, testes, prostate.
• Reactome Pathway: Regulation of CDH11 gene transcription (R-HSA-9762293)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[1]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Genetic Variation	[2]
Bone marrow failure syndrome	DISVUY1J	Strong	Biomarker	[3]
Dyskeratosis congenita	DISSXV0K	Strong	Posttranslational Modification	[3]
Early-onset Lafora body disease	DISU9G28	Strong	Autosomal recessive	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[6]

2 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 PR domain zinc finger protein 8 (PRDM8).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of PR domain zinc finger protein 8 (PRDM8).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of PR domain zinc finger protein 8 (PRDM8).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PR domain zinc finger protein 8 (PRDM8).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of PR domain zinc finger protein 8 (PRDM8).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of PR domain zinc finger protein 8 (PRDM8).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of PR domain zinc finger protein 8 (PRDM8).	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of PR domain zinc finger protein 8 (PRDM8).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of PR domain zinc finger protein 8 (PRDM8).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of PR domain zinc finger protein 8 (PRDM8).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of PR domain zinc finger protein 8 (PRDM8).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of PR domain zinc finger protein 8 (PRDM8).	[18]

References

• [1] Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides.Front Immunol. 2019 Apr 15;10:791. doi: 10.3389/fimmu.2019.00791. eCollection 2019.
• [2] Common origin of sequential cutaneous CD30+ lymphoproliferations with nodal involvement evidenced by genome-wide clonal evolution.Histopathology. 2019 Mar;74(4):654-662. doi: 10.1111/his.13783. Epub 2019 Jan 31.
• [3] DNA methylation in PRDM8 is indicative for dyskeratosis congenita.Oncotarget. 2016 Mar 8;7(10):10765-72. doi: 10.18632/oncotarget.7458.
• [4] Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly. Neuron. 2012 Jan 26;73(2):292-303. doi: 10.1016/j.neuron.2011.09.035.
• [5] Prenatal phthalate exposure and altered patterns of DNA methylation in cord blood.Environ Mol Mutagen. 2017 Jul;58(6):398-410. doi: 10.1002/em.22095. Epub 2017 May 28.
• [6] PRDM8 exhibits antitumor activities toward hepatocellular carcinoma by targeting NAP1L1.Hepatology. 2018 Sep;68(3):994-1009. doi: 10.1002/hep.29890. Epub 2018 May 21.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [10] 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.
• [11] 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.
• [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] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [15] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] 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.
• [18] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.