Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5X8A3O)

• DOT Name: Charged multivesicular body protein 4c (CHMP4C)
• Synonyms: Chromatin-modifying protein 4c; CHMP4c; SNF7 homolog associated with Alix 3; SNF7-3; hSnf7-3; Vacuolar protein sorting-associated protein 32-3; Vps32-3; hVps32-3
• Gene Name: CHMP4C
• Related Disease:
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Epithelial ovarian cancer
• UniProt ID: CHM4C_HUMAN
• PDB ID: 3C3R; 5MK3; 5V3R; 5WA1
• Pfam ID: PF03357
• Sequence:
  MSKLGKFFKGGGSSKSRAAPSPQEALVRLRETEEMLGKKQEYLENRIQREIALAKKHGTQ
  NKRAALQALKRKKRFEKQLTQIDGTLSTIEFQREALENSHTNTEVLRNMGFAAKAMKSVH
  ENMDLNKIDDLMQEITEQQDIAQEISEAFSQRVGFGDDFDEDELMAELEELEQEELNKKM
  TNIRLPNVPSSSLPAQPNRKPGMSSTARRSRAASSQRAEEEDDDIKQLAAWAT
• Function: Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). Key component of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage: upon phosphorylation by AURKB, together with ZFYVE19/ANCHR, retains abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis. Deactivation of AURKB results in dephosphorylation of CHMP4C followed by its dissociation from ANCHR and VPS4 and subsequent abscission. ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Involved in HIV-1 p6- and p9-dependent virus release. CHMP4A/B/C are required for the exosomal release of SDCBP, CD63 and syndecan.
• Tissue Specificity: Expressed in heart, spleen and kidney.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Necroptosis (hsa04217)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  Pyroptosis (R-HSA-5620971)
  Endosomal Sorting Complex Required For Transport (ESCRT) (R-HSA-917729)
  HCMV Late Events (R-HSA-9610379)
  Late endosomal microautophagy (R-HSA-9615710)
  Sealing of the nuclear envelope (NE) by ESCRT-III (R-HSA-9668328)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9679504)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9694676)
  Budding and maturation of HIV virion (R-HSA-162588)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Charged multivesicular body protein 4c (CHMP4C).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Charged multivesicular body protein 4c (CHMP4C).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Charged multivesicular body protein 4c (CHMP4C).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Charged multivesicular body protein 4c (CHMP4C).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Charged multivesicular body protein 4c (CHMP4C).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Charged multivesicular body protein 4c (CHMP4C).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Charged multivesicular body protein 4c (CHMP4C).	[12]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Charged multivesicular body protein 4c (CHMP4C).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Charged multivesicular body protein 4c (CHMP4C).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Charged multivesicular body protein 4c (CHMP4C).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Charged multivesicular body protein 4c (CHMP4C).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Charged multivesicular body protein 4c (CHMP4C).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Charged multivesicular body protein 4c (CHMP4C).	[15]

References

• [1] A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability.Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):E8900-E8908. doi: 10.1073/pnas.1805504115. Epub 2018 Sep 4.
• [2] CHMP4C Disruption Sensitizes the Human Lung Cancer Cells to Irradiation.Int J Mol Sci. 2015 Dec 24;17(1):18. doi: 10.3390/ijms17010018.
• [3] A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.Nat Genet. 2019 May;51(5):815-823. doi: 10.1038/s41588-019-0395-x. Epub 2019 May 1.
• [4] Proteomic analysis of urinary extracellular vesicles from high Gleason score prostate cancer.Sci Rep. 2017 Feb 17;7:42961. doi: 10.1038/srep42961.
• [5] GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.Nat Genet. 2013 Apr;45(4):362-70, 370e1-2. doi: 10.1038/ng.2564.
• [6] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.
• [17] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.