Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPOO9LK)

• DOT Name: Centromere protein H (CENPH)
• Synonyms: CENP-H; Interphase centromere complex protein 35
• Gene Name: CENPH
• Related Disease:
  Advanced cancer
  Anal intraepithelial neoplasia
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Hypopharyngeal carcinoma
  Hypopharyngeal squamous cell carcinoma
  Hypopharynx cancer
  Neoplasm
  Renal cell carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Nasopharyngeal carcinoma
  Cervical Intraepithelial neoplasia
  Colorectal neoplasm
• UniProt ID: CENPH_HUMAN
• PDB ID: 7PB4; 7PKN; 7QOO; 7R5S; 7R5V; 7XHN; 7XHO; 7YWX; 7YYH
• Pfam ID: PF05837
• Sequence:
  MEEQPQMQDADEPADSGGEGRAGGPPQVAGAQAACSEDRMTLLLRLRAQTKQQLLEYKSM
  VDASEEKTPEQIMQEKQIEAKIEDLENEIEEVKVAFEIKKLALDRMRLSTALKKNLEKIS
  RQSSVLMDNMKHLLELNKLIMKSQQESWDLEEKLLDIRKKRLQLKQASESKLLEIQTEKN
  KQKIDLDSMENSERIKIIRQNLQMEIKITTVIQHVFQNLILGSKVNWAEDPALKEIVLQL
  EKNVDMM
• Function: Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. Required for chromosome congression and efficiently align the chromosomes on a metaphase plate.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Hypopharyngeal carcinoma	DISLOSB4	Strong	Biomarker	[7]
Hypopharyngeal squamous cell carcinoma	DISDDD65	Strong	Altered Expression	[7]
Hypopharynx cancer	DISW5DOZ	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[4]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[2]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[8]
Cervical Intraepithelial neoplasia	DISXP757	Limited	Altered Expression	[9]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Centromere protein H (CENPH).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Centromere protein H (CENPH).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centromere protein H (CENPH).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Centromere protein H (CENPH).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Centromere protein H (CENPH).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centromere protein H (CENPH).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centromere protein H (CENPH).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Centromere protein H (CENPH).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Centromere protein H (CENPH).	[17]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Centromere protein H (CENPH).	[18]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Centromere protein H (CENPH).	[19]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Centromere protein H (CENPH).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein H (CENPH).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centromere protein H (CENPH).	[23]

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 decreases the methylation of Centromere protein H (CENPH).	[21]

References

• [1] Overexpression of CENP-H as a novel prognostic biomarker for human hepatocellular carcinoma progression and patient survival.Oncol Rep. 2013 Nov;30(5):2238-44. doi: 10.3892/or.2013.2675. Epub 2013 Aug 20.
• [2] Increased expression of CENP-H gene in human oral squamous cell carcinomas harboring high-proliferative activity.Oncol Rep. 2006 Nov;16(5):1071-5.
• [3] Overexpression of centromere protein H is significantly associated with breast cancer progression and overall patient survival.Chin J Cancer. 2011 Sep;30(9):627-37. doi: 10.5732/cjc.010.10599.
• [4] Upregulation of centromere protein H is associated with progression of renal cell carcinoma.J Mol Histol. 2015 Oct;46(4-5):377-85. doi: 10.1007/s10735-015-9635-2. Epub 2015 Aug 7.
• [5] CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer.J Cancer. 2017 Jul 15;8(12):2163-2172. doi: 10.7150/jca.19940. eCollection 2017.
• [6] Combined evaluation of centromere protein H and Ki-67 as prognostic biomarker for patients with gastric carcinoma.Eur J Surg Oncol. 2013 Feb;39(2):141-9. doi: 10.1016/j.ejso.2012.08.023. Epub 2012 Sep 19.
• [7] Role of centromere protein H and Ki67 in relapse-free survival of patients after primary surgery for hypopharyngeal cancer.Asian Pac J Cancer Prev. 2012;13(3):821-5. doi: 10.7314/apjcp.2012.13.3.821.
• [8] Sp1 and Sp3 are involved in the full transcriptional activity of centromere protein H in human nasopharyngeal carcinoma cells.FEBS J. 2012 Aug;279(15):2714-26. doi: 10.1111/j.1742-4658.2012.08654.x. Epub 2012 Jun 25.
• [9] Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy.Cancer Res. 2005 Jun 1;65(11):4683-9. doi: 10.1158/0008-5472.CAN-04-3613.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] 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.
• [17] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [18] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [19] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [20] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [21] 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.
• [22] 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.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.