Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDP2O9X)

• DOT Name: EZH inhibitory protein (EZHIP)
• Gene Name: EZHIP
• Related Disease:
  Brain cancer
  Ependymoma
  Neoplasm
• UniProt ID: EZHIP_HUMAN
• Sequence:
  MATQSDMEKEQKHQQDEGQGGLNNETALASGDACGTGNQDPAASVTTVSSQASPSGGAAL
  SSSTAGSSAAAATSAAIFITDEASGLPIIAAVLTERHSDRQDCRSPHEVFGCVVPEGGSQ
  AAVGPQKATGHADEHLAQTKSPGNSRRRKQPCRNQAAPAQKPPGRRLFPEPLPPSSPGFR
  PSSYPCSGASTSSQATQPGPALLSHASEARPATRSRITLVASALRRRASGPGPVIRGCTA
  QPGPAFPHRATHLDPARLSPESAPGPARRGRASVPGPARRGCDSAPGPARRGRDSAPVSA
  PRGRDSAPGSARRGRDSAPGPALRVRTARSDAGHRSTSTTPGTGLRSRSTQQRSALLSRR
  SLSGSADENPSCGTGSERLAFQSRSGSPDPEVPSRASPPVWHAVRMRASSPSPPGRFFLP
  IPQQWDESSSSSYASNSSSPSRSPGLSPSSPSPEFLGLRSISTPSPESLRYALMPEFYAL
  SPVPPEEQAEIESTAHPATPPEP
• Function: Inhibits PRC2/EED-EZH1 and PRC2/EED-EZH2 complex function by inhibiting EZH1/EZH2 methyltransferase activity, thereby causing down-regulation of histone H3 trimethylation on 'Lys-27' (H3K27me3). Probably inhibits methyltransferase activity by limiting the stimulatory effect of cofactors such as AEBP2 and JARID2. Inhibits H3K27me3 deposition during spermatogenesis and oogenesis.
• Tissue Specificity: In testis, detected in male germ cells inside the seminiferous tubules, especially in spermatogonia and round spermatids (at protein level) . In the ovary, expressed in primordial follicles and oocytes but not the external follicle cells (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brain cancer	DISBKFB7	Strong	Genetic Variation	[1]
Ependymoma	DISUMRNZ	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]

3 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 EZH inhibitory protein (EZHIP).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of EZH inhibitory protein (EZHIP).	[4]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of EZH inhibitory protein (EZHIP).	[5]

References

• [1] Identification of a novel, recurrent MBTD1-CXorf67 fusion in low-grade endometrial stromal sarcoma.Int J Cancer. 2014 Mar 1;134(5):1112-22. doi: 10.1002/ijc.28440. Epub 2013 Sep 4.
• [2] EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.Neuro Oncol. 2019 Jul 11;21(7):878-889. doi: 10.1093/neuonc/noz058.
• [3] 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.
• [4] 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.
• [5] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.