Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7ZVR57)

• DOT Name: HAUS augmin-like complex subunit 6 (HAUS6)
• Gene Name: HAUS6
• Related Disease:
  Familial prostate carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer, hereditary, 1
  Prostate carcinoma
  Basal cell carcinoma
  Basal cell neoplasm
• UniProt ID: HAUS6_HUMAN
• PDB ID: 7SQK
• Pfam ID: PF14661
• Sequence:
  MSSASVTAFEKEHLWMYLQALGFEPGPATIACGKIVSHTHLGVNMFDKLNRDAFHIISYF
  LFQVLDQSLTKEVFKFCWPPFDQKSDTEFRKHCCEWIKRISGECGSSFPQVVGSLFLSPG
  GPKFIHLMYHFARFVAMKYIKSNSKNSSHHFVETFNIKPQDLHKCIARCHFARSRFLQIL
  QRQDCVTQKYQENAQLSVKQVRNLRSECIGLENQIKKMEPYDDHSNMEEKIQKVRSLWAS
  VNETLMFLEKEREVVSSVLSLVNQYALDGTNVAINIPRLLLDKIEKQMFQLHIGNVYEAG
  KLNLLTVIQLLNEVLKVMKYERCQADQARLTVDLHYLEKETKFQKERLSDLKHMRYRIKD
  DLTTIRHSVVEKQGEWHKKWKEFLGLSPFSLIKGWTPSVDLLPPMSPLSFDPASEEVYAK
  SILCQYPASLPDAHKQHNQENGCRGDSDTLGALHDLANSPASFLSQSVSSSDRNSVTVLE
  KDTKMGTPKEKNEAISKKIPEFEVENSPLSDVAKNTESSAFGGSLPAKKSDPFQKEQDHL
  VEEVARAVLSDSPQLSEGKEIKLEELIDSLGSNPFLTRNQIPRTPENLITEIRSSWRKAI
  EMEENRTKEPIQMDAEHREVLPESLPVLHNQREFSMADFLLETTVSDFGQSHLTEEKVIS
  DCECVPQKHVLTSHIDEPPTQNQSDLLNKKVICKQDLECLAFTKLSETSRMETFSPAVGN
  RIDVMGGSEEEFMKILDHLEVSCNKPSTNKTMLWNSFQISSGISSKSFKDNDFGILHETL
  PEEVGHLSFNSSSSSEANFKLEPNSPMHGGTLLEDVVGGRQTTPESDFNLQALRSRYEAL
  KKSLSKKREESYLSNSQTPERHKPELSPTPQNVQTDDTLNFLDTCDLHTEHIKPSLRTSI
  GERKRSLSPLIKFSPVEQRLRTTIACSLGELPNLKEEDILNKSLDAKEPPSDLTR
• Function: Contributes to mitotic spindle assembly, maintenance of centrosome integrity and completion of cytokinesis as part of the HAUS augmin-like complex. Promotes the nucleation of microtubules from the spindle through recruitment of NEDD1 and gamma-tubulin.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[1]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[3]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[3]

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 HAUS augmin-like complex subunit 6 (HAUS6).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of HAUS augmin-like complex subunit 6 (HAUS6).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of HAUS augmin-like complex subunit 6 (HAUS6).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of HAUS augmin-like complex subunit 6 (HAUS6).	[17]

References

• [1] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [2] 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.
• [3] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [4] 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.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] 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.
• [9] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [12] 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.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.