Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT52A8BJ)

• DOT Name: ATPase MORC2 (MORC2)
• Synonyms: EC 3.6.1.-; MORC family CW-type zinc finger protein 2; Zinc finger CW-type coiled-coil domain protein 1
• Gene Name: MORC2
• Related Disease:
  Charcot-Marie-Tooth disease axonal type 2Z
  Lung cancer
  Lung carcinoma
  Advanced cancer
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 1
  Charcot-Marie-Tooth disease type 1A
  Charcot-Marie-Tooth disease type 1B
  Charcot-Marie-Tooth disease type 2
  Cholangiocarcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Congenital contractural arachnodactyly
  Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy
  Gastric cancer
  Nervous system disease
  Non-small-cell lung cancer
  Spinal muscular atrophy
  Stomach cancer
  Triple negative breast cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Neoplasm
  Hepatocellular carcinoma
  Leigh syndrome
  Neurofibromatosis type 2
• UniProt ID: MORC2_HUMAN
• PDB ID: 5OF9; 5OFA; 5OFB
• EC Number: 3.6.1.-
• Pfam ID: PF13589 ; PF17942 ; PF07496
• Sequence:
  MAFTNYSSLNRAQLTFEYLHTNSTTHEFLFGALAELVDNARDADATRIDIYAERREDLRG
  GFMLCFLDDGAGMDPSDAASVIQFGKSAKRTPESTQIGQYGNGLKSGSMRIGKDFILFTK
  KEDTMTCLFLSRTFHEEEGIDEVIVPLPTWNARTREPVTDNVEKFAIETELIYKYSPFRT
  EEEVMTQFMKIPGDSGTLVIIFNLKLMDNGEPELDIISNPRDIQMAETSPEGTKPERRSF
  RAYAAVLYIDPRMRIFIHGHKVQTKRLSCCLYKPRMYKYTSSRFKTRAEQEVKKAEHVAR
  IAEEKAREAESKARTLEVRLGGDLTRDSRVMLRQVQNRAITLRREADVKKRIKEAKQRAL
  KEPKELNFVFGVNIEHRDLDGMFIYNCSRLIKMYEKVGPQLEGGMACGGVVGVVDVPYLV
  LEPTHNKQDFADAKEYRHLLRAMGEHLAQYWKDIAIAQRGIIKFWDEFGYLSANWNQPPS
  SELRYKRRRAMEIPTTIQCDLCLKWRTLPFQLSSVEKDYPDTWVCSMNPDPEQDRCEASE
  QKQKVPLGTFRKDMKTQEEKQKQLTEKIRQQQEKLEALQKTTPIRSQADLKKLPLEVTTR
  PSTEEPVRRPQRPRSPPLPAVIRNAPSRPPSLPTPRPASQPRKAPVISSTPKLPALAARE
  EASTSRLLQPPEAPRKPANTLVKTASRPAPLVQQLSPSLLPNSKSPREVPSPKVIKTPVV
  KKTESPIKLSPATPSRKRSVAVSDEEEVEEEAERRKERCKRGRFVVKEEKKDSNELSDSA
  GEEDSADLKRAQKDKGLHVEVRVNREWYTGRVTAVEVGKHVVRWKVKFDYVPTDTTPRDR
  WVEKGSEDVRLMKPPSPEHQSLDTQQEGGEEEVGPVAQQAIAVAEPSTSECLRIEPDTTA
  LSTNHETIDLLVQILRNCLRYFLPPSFPISKKQLSAMNSDELISFPLKEYFKQYEVGLQN
  LCNSYQSRADSRAKASEESLRTSERKLRETEEKLQKLRTNIVALLQKVQEDIDINTDDEL
  DAYIEDLITKGD
• Function: Essential for epigenetic silencing by the HUSH (human silencing hub) complex. Recruited by HUSH to target site in heterochromatin, the ATPase activity and homodimerization are critical for HUSH-mediated silencing. Represses germ cell-related genes and L1 retrotransposons in collaboration with SETDB1 and the HUSH complex, the silencing is dependent of repressive epigenetic modifications, such as H3K9me3 mark. Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression. During DNA damage response, regulates chromatin remodeling through ATP hydrolysis. Upon DNA damage, is phosphorylated by PAK1, both colocalize to chromatin and induce H2AX expression. ATPase activity is required and dependent of phosphorylation by PAK1 and presence of DNA. Recruits histone deacetylases, such as HDAC4, to promoter regions, causing local histone H3 deacetylation and transcriptional repression of genes such as CA9. Exhibits a cytosolic function in lipogenesis, adipogenic differentiation, and lipid homeostasis by increasing the activity of ACLY, possibly preventing its dephosphorylation.
• Tissue Specificity: Highly expressed in smooth muscle, pancreas and testis.
• Reactome Pathway: Fatty acyl-CoA biosynthesis (R-HSA-75105)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease axonal type 2Z	DISPWCA1	Definitive	Autosomal dominant	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[2]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[4]
Charcot-Marie-Tooth disease type 1	DIS56F9A	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 1A	DISSRZG7	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 1B	DISJRS1V	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Biomarker	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[6]
Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy	DIS9DBAD	Strong	Autosomal dominant	[8]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[9]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[11]
Spinal muscular atrophy	DISTLKOB	Strong	Genetic Variation	[12]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[9]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[10]
Breast cancer	DIS7DPX1	Disputed	Altered Expression	[11]
Breast carcinoma	DIS2UE88	Disputed	Altered Expression	[11]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Disputed	Altered Expression	[13]
Liver cancer	DISDE4BI	Disputed	Altered Expression	[13]
Neoplasm	DISZKGEW	Disputed	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[3]
Leigh syndrome	DISWQU45	Limited	Autosomal dominant	[1]
Neurofibromatosis type 2	DISI8ECS	Limited	Biomarker	[3]

8 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 ATPase MORC2 (MORC2).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATPase MORC2 (MORC2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATPase MORC2 (MORC2).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of ATPase MORC2 (MORC2).	[17]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of ATPase MORC2 (MORC2).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of ATPase MORC2 (MORC2).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ATPase MORC2 (MORC2).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATPase MORC2 (MORC2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of ATPase MORC2 (MORC2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ATPase MORC2 (MORC2).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of ATPase MORC2 (MORC2).	[20]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] MORC2 Enhances Tumor Growth by Promoting Angiogenesis and Tumor-Associated Macrophage Recruitment via Wnt/-Catenin in Lung Cancer.Cell Physiol Biochem. 2018;51(4):1679-1694. doi: 10.1159/000495673. Epub 2018 Nov 30.
• [3] Epigenetic restriction of Hippo signaling by MORC2 underlies stemness of hepatocellular carcinoma cells.Cell Death Differ. 2018 Dec;25(12):2086-2100. doi: 10.1038/s41418-018-0095-6. Epub 2018 Mar 19.
• [4] Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations.Hum Mol Genet. 2019 May 15;28(10):1629-1644. doi: 10.1093/hmg/ddz006.
• [5] Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.Nat Genet. 2017 Jul;49(7):1035-1044. doi: 10.1038/ng.3878. Epub 2017 Jun 5.
• [6] MORC2 promotes cell growth and metastasis in human cholangiocarcinoma and is negatively regulated by miR-186-5p.Aging (Albany NY). 2019 Jun 9;11(11):3639-3649. doi: 10.18632/aging.102003.
• [7] MORC2 promotes development of an aggressive colorectal cancer phenotype through inhibition of NDRG1.Cancer Sci. 2019 Jan;110(1):135-146. doi: 10.1111/cas.13863. Epub 2018 Dec 21.
• [8] MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs. Ann Neurol. 2016 Mar;79(3):419-27. doi: 10.1002/ana.24575. Epub 2016 Jan 13.
• [9] MORC2 regulates C/EBP-mediated cell differentiation via sumoylation.Cell Death Differ. 2019 Oct;26(10):1905-1917. doi: 10.1038/s41418-018-0259-4. Epub 2019 Jan 15.
• [10] Cancer-Associated MORC2-Mutant M276I Regulates an hnRNPM-Mediated CD44 Splicing Switch to Promote Invasion and Metastasis in Triple-Negative Breast Cancer.Cancer Res. 2018 Oct 15;78(20):5780-5792. doi: 10.1158/0008-5472.CAN-17-1394. Epub 2018 Aug 9.
• [11] Aberrant high expression level of MORC2 is a common character in multiple cancers.Hum Pathol. 2018 Jun;76:58-67. doi: 10.1016/j.humpath.2018.03.011. Epub 2018 Mar 16.
• [12] Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms.Nat Commun. 2018 Feb 13;9(1):651. doi: 10.1038/s41467-018-03045-x.
• [13] MORC2, a novel oncogene, is upregulated in liver cancer and contributes to proliferation, metastasis and chemoresistance.Int J Oncol. 2018 Jul;53(1):59-72. doi: 10.3892/ijo.2018.4333. Epub 2018 Mar 27.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] 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.
• [16] 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.
• [17] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [18] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [19] 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.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.