Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRASC9G)

• DOT Name: N-terminal EF-hand calcium-binding protein 3 (NECAB3)
• Synonyms: Amyloid-beta A4 protein-binding family A member 2-binding protein; Nek2-interacting protein 1; Neuronal calcium-binding protein 3; X11L-binding protein 51
• Gene Name: NECAB3
• Related Disease:
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Non-small-cell lung cancer
  Advanced cancer
• UniProt ID: NECA3_HUMAN
• Pfam ID: PF03992 ; PF13202
• Sequence:
  MACAGLLTVCLLRPPAPQPQPQTPRHPQLAPDPGPAGHTLFQDVFRRADKNDDGKLSFEE
  FQNYFADGVLSLGELQELFSGIDGHLTDNLETEKLCDYFSEHLGVYRPVLAALESLNRAV
  LAAMDATKLEYERASKVDQFVTRFLLRETVSQLQALQSSLEGASDTLEAQAHGWRSDAES
  VEAQSRLCGSRRAGRRALRSVSRSSTWSPGSSDTGRSSEAEMQWRLQVNRLQELIDQLEC
  KVRAVGPGPHKGGPSWYPPEPGPCWRPGPHSVPSQAPRLEPLREEDLAKGPDLHILMAQR
  QVQVAEEGLQDFHRALRCYVDFTGAQSHCLHVSAQKMLDGASFTLYEFWQDEASWRRHQQ
  SPGSKAFQRILIDHLRAPDTLTTVFFPASWWIMNNN
• Function: Inhibits the interaction of APBA2 with amyloid-beta precursor protein (APP), and hence allows formation of amyloid-beta. May enhance the activity of HIF1A and thus promote glycolysis under normoxic conditions; the function requires its ABM domain and may implicate the stabilization of the interaction between HIF1AN and APBA3.
• Tissue Specificity: Strongly expressed in heart and skeletal muscle, moderately in brain and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]

4 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 N-terminal EF-hand calcium-binding protein 3 (NECAB3).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of N-terminal EF-hand calcium-binding protein 3 (NECAB3).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of N-terminal EF-hand calcium-binding protein 3 (NECAB3).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of N-terminal EF-hand calcium-binding protein 3 (NECAB3).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N-terminal EF-hand calcium-binding protein 3 (NECAB3).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-terminal EF-hand calcium-binding protein 3 (NECAB3).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of N-terminal EF-hand calcium-binding protein 3 (NECAB3).	[10]

References

• [1] Isolation and expression analysis of Alzheimer's disease-related gene xb51 in zebrafish.Dev Dyn. 2008 Dec;237(12):3921-6. doi: 10.1002/dvdy.21806.
• [2] NIP1/DUOXA1 expression in epithelial breast cancer cells: regulation of cell adhesion and actin dynamics.Breast Cancer Res Treat. 2010 Feb;119(3):773-86. doi: 10.1007/s10549-009-0372-7. Epub 2009 Mar 26.
• [3] GNAS-AS1/miR-4319/NECAB3 axis promotes migration and invasion of non-small cell lung cancer cells by altering macrophage polarization.Funct Integr Genomics. 2020 Jan;20(1):17-28. doi: 10.1007/s10142-019-00696-x. Epub 2019 Jul 3.
• [4] NECAB3 Promotes Activation of Hypoxia-inducible factor-1 during Normoxia and Enhances Tumourigenicity of Cancer Cells.Sci Rep. 2016 Mar 7;6:22784. doi: 10.1038/srep22784.
• [5] 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.
• [6] 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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.