Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ6E2C8)

• DOT Name: Microtubule organization protein AKNA (AKNA)
• Synonyms: AT-hook-containing transcription factor
• Gene Name: AKNA
• Related Disease:
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Knee osteoarthritis
• UniProt ID: AKNA_HUMAN
• Pfam ID: PF12443
• Sequence:
  MASSETEIRWAEPGLGKGPQRRRWAWAEDKRDVDRSSSQSWEEERLFPNATSPELLEDFR
  LAQQHLPPLEWDPHPQPDGHQDSESGETSGEEAEAEDVDSPASSHEPLAWLPQQGRQLDM
  TEEEPDGTLGSLEVEEAGESSSRLGYEAGLSLEGHGNTSPMALGHGQARGWVASGEQASG
  DKLSEHSEVNPSVELSPARSWSSGTVSLDHPSDSLDSTWEGETDGPQPTALAETLPEGPS
  HHLLSPDGRTGGSVARATPMEFQDSSAPPAQSPQHATDRWRRETTRFFCPQPKEHIWKQT
  KTSPKPLPSRFIGSISPLNPQPRPTRQGRPLPRQGATLAGRSSSNAPKYGRGQLNYPLPD
  FSKVGPRVRFPKDESYRPPKSRSHNRKPQAPARPLIFKSPAEIVQEVLLSSGEAALAKDT
  PPAHPITRVPQEFQTPEQATELVHQLQEDYHRLLTKYAEAENTIDQLRLGAKVNLFSDPP
  QPNHSIHTGMVPQGTKVLSFTIPQPRSAEWWPGPAEDPQASAASGWPSARGDLSPSSLTS
  MPTLGWLPENRDISEDQSSAEQTQALASQASQFLAKVESFERLIQAGRLMPQDQVKGFQR
  LKAAHAALEEEYLKACREQHPAQPLAGSKGTPGRFDPRRELEAEIYRLGSCLEELKEHID
  QTQQEPEPPGSDSALDSTPALPCLHQPTHLPAPSGQAPMPAIKTSCPEPATTTAAASTGP
  CPLHVNVEVSSGNSEVEDRPQDPLARLRHKELQMEQVYHGLMERYLSVKSLPEAMRMEEE
  EEGEEEEEEEGGGDSLEVDGVAATPGKAEATRVLPRQCPVQAEKSHGAPLEEATEKMVSM
  KPPGFQASLARDGHMSGLGKAEAAPPGPGVPPHPPGTKSAASHQSSMTSLEGSGISERLP
  QKPLHRGGGPHLEETWMASPETDSGFVGSETSRVSPLTQTPEHRLSHISTAGTLAQPFAA
  SVPRDGASYPKARGSLIPRRATEPSTPRSQAQRYLSSPSGPLRQRAPNFSLERTLAAEMA
  VPGSEFEGHKRISEQPLPNKTISPPPAPAPAAAPLPCGPTETIPSFLLTRAGRDQAICEL
  QEEVSRLRLRLEDSLHQPLQGSPTRPASAFDRPARTRGRPADSPATWGSHYGSKSTERLP
  GEPRGEEQIVPPGRQRARSSSVPREVLRLSLSSESELPSLPLFSEKSKTTKDSPQAARDG
  KRGVGSAGWPDRVTFRGQYTGHEYHVLSPKAVPKGNGTVSCPHCRPIRTQDAGGAVTGDP
  LGPPPADTLQCPLCGQVGSPPEADGPGSATSGAEKATTRRKASSTPSPKQRSKQAGSSPR
  PPPGLWYLATAPPAPAPPAFAYISSVPIMPYPPAAVYYAPAGPTSAQPAAKWPPTASPPP
  ARRHRHSIQLDLGDLEELNKALSRAVQAAESVRSTTRQMRSSLSADLRQAHSLRGSCLF
• Function: Centrosomal protein that plays a key role in cell delamination by regulating microtubule organization. Required for the delamination and retention of neural stem cells from the subventricular zone during neurogenesis. Also regulates the epithelial-to-mesenchymal transition in other epithelial cells. Acts by increasing centrosomal microtubule nucleation and recruiting nucleation factors and minus-end stabilizers, thereby destabilizing microtubules at the adherens junctions and mediating constriction of the apical endfoot. In addition, may also act as a transcription factor that specifically activates the expression of the CD40 receptor and its ligand CD40L/CD154, two cell surface molecules on lymphocytes that are critical for antigen-dependent-B-cell development. Binds to A/T-rich promoters. It is unclear how it can both act as a microtubule organizer and as a transcription factor; additional evidences are required to reconcile these two apparently contradictory functions (Probable).
• Tissue Specificity: Predominantly expressed by lymphoid tissues. Highly expressed in the spleen, lymph nodes and peripheral blood leukocytes, expressed at lower level in the thymus. Mainly expressed by germinal center B-lymphocytes, a stage in which receptor and ligand interactions are crucial for B-lymphocyte maturation. Expressed by B- and T-lymphocytes, Natural killer cells and CD1a(+)CD14(-) but not CD1a(-)CD14(+) dendritic cells. Weakly or not expressed in fetal liver and in adult bone marrow.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[2]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Microtubule organization protein AKNA (AKNA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Microtubule organization protein AKNA (AKNA).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Microtubule organization protein AKNA (AKNA).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Microtubule organization protein AKNA (AKNA).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Microtubule organization protein AKNA (AKNA).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Microtubule organization protein AKNA (AKNA).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Microtubule organization protein AKNA (AKNA).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Microtubule organization protein AKNA (AKNA).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Microtubule organization protein AKNA (AKNA).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Microtubule organization protein AKNA (AKNA).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Microtubule organization protein AKNA (AKNA).	[16]

2 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 Microtubule organization protein AKNA (AKNA).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Microtubule organization protein AKNA (AKNA).	[14]

References

• [1] HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes.Cancer Res. 2011 Jan 15;71(2):349-59. doi: 10.1158/0008-5472.CAN-10-2550. Epub 2011 Jan 11.
• [2] The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA.Cancers (Basel). 2018 Dec 17;10(12):521. doi: 10.3390/cancers10120521.
• [3] The association of AKNA gene polymorphisms with knee osteoarthritis suggests the relevance of this immune response regulator in the disease genetic susceptibility.Mol Biol Rep. 2018 Apr;45(2):151-161. doi: 10.1007/s11033-018-4148-1. Epub 2018 Jan 24.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] 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.
• [8] 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.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.