Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ6WSKW)

• DOT Name: Akirin-2 (AKIRIN2)
• Gene Name: AKIRIN2
• Related Disease:
  Advanced cancer
  Cholangiocarcinoma
  Choriocarcinoma
  Colorectal carcinoma
  Congenital contractural arachnodactyly
  Gestational trophoblastic neoplasia
  Hepatocellular carcinoma
  Hydatidiform mole
  Lymphoma
  Neoplasm
  Syndactyly
  Adenocarcinoma
  Rectal carcinoma
  Rheumatoid arthritis
  Squamous cell carcinoma
• UniProt ID: AKIR2_HUMAN
• PDB ID: 7NHT
• Sequence:
  MACGATLKRTLDFDPLLSPASPKRRRCAPLSAPTSAAASPLSAAAATAASFSAAAASPQK
  YLRMEPSPFGDVSSRLTTEQILYNIKQEYKRMQKRRHLETSFQQTDPCCTSDAQPHAFLL
  SGPASPGTSSAASSPLKKEQPLFTLRQVGMICERLLKEREEKVREEYEEILNTKLAEQYD
  AFVKFTHDQIMRRYGEQPASYVS
• Function: Molecular adapter that acts as a bridge between a variety of multiprotein complexes, and which is involved in embryonic development, immunity, myogenesis and brain development. Plays a key role in nuclear protein degradation by promoting import of proteasomes into the nucleus: directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end, bridging them together and mediating the import of pre-assembled proteasome complexes through the nuclear pore. Involved in innate immunity by regulating the production of interleukin-6 (IL6) downstream of Toll-like receptor (TLR): acts by bridging the NF-kappa-B inhibitor NFKBIZ and the SWI/SNF complex, leading to promote induction of IL6. Also involved in adaptive immunity by promoting B-cell activation. Involved in brain development: required for the survival and proliferation of cerebral cortical progenitor cells. Involved in myogenesis: required for skeletal muscle formation and skeletal development, possibly by regulating expression of muscle differentiation factors. Also plays a role in facilitating interdigital tissue regression during limb development.
• Tissue Specificity: Widely expressed with the highest expression in peripheral blood leukocytes.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[2]
Choriocarcinoma	DISDBVNL	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[2]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Hydatidiform mole	DISKNP7O	Strong	Altered Expression	[3]
Lymphoma	DISN6V4S	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Syndactyly	DISZK2BT	Strong	Biomarker	[6]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[7]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[9]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Akirin-2 (AKIRIN2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Akirin-2 (AKIRIN2).	[23]

18 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 Akirin-2 (AKIRIN2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Akirin-2 (AKIRIN2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Akirin-2 (AKIRIN2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Akirin-2 (AKIRIN2).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Akirin-2 (AKIRIN2).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Akirin-2 (AKIRIN2).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Akirin-2 (AKIRIN2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Akirin-2 (AKIRIN2).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Akirin-2 (AKIRIN2).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Akirin-2 (AKIRIN2).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Akirin-2 (AKIRIN2).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Akirin-2 (AKIRIN2).	[21]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Akirin-2 (AKIRIN2).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Akirin-2 (AKIRIN2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Akirin-2 (AKIRIN2).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Akirin-2 (AKIRIN2).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Akirin-2 (AKIRIN2).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Akirin-2 (AKIRIN2).	[27]

References

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• [2] Akirin2 is modulated by miR-490-3p and facilitates angiogenesis in cholangiocarcinoma through the IL-6/STAT3/VEGFA signaling pathway.Cell Death Dis. 2019 Mar 18;10(4):262. doi: 10.1038/s41419-019-1506-4.
• [3] FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.Am J Pathol. 2015 Jul;185(7):2038-48. doi: 10.1016/j.ajpath.2015.03.011.
• [4] FBI-1 enhances ETS-1 signaling activity and promotes proliferation of human colorectal carcinoma cells.PLoS One. 2014 May 23;9(5):e98041. doi: 10.1371/journal.pone.0098041. eCollection 2014.
• [5] MicroRNA-137 represses FBI-1 to inhibit proliferation and in vitro invasion and migration of hepatocellular carcinoma cells.Tumour Biol. 2016 Oct;37(10):13995-14008. doi: 10.1007/s13277-016-5230-8. Epub 2016 Aug 4.
• [6] An essential role for the nuclear protein Akirin2 in mouse limb interdigital tissue regression.Sci Rep. 2018 Aug 16;8(1):12240. doi: 10.1038/s41598-018-30801-2.
• [7] Proto-oncogene FBI-1 represses transcription of p21CIP1 by inhibition of transcription activation by p53 and Sp1.J Biol Chem. 2009 May 8;284(19):12633-44. doi: 10.1074/jbc.M809794200. Epub 2009 Feb 25.
• [8] Prognostic value of nuclear FBI-1 in patients with rectal cancer with or without preoperative radiotherapy.Oncol Lett. 2019 Nov;18(5):5301-5309. doi: 10.3892/ol.2019.10890. Epub 2019 Sep 19.
• [9] The transcription factor FBI-1/OCZF/LRF is expressed in osteoclasts and regulates RANKL-induced osteoclast formation in vitro and in vivo.Arthritis Rheum. 2011 Sep;63(9):2744-54. doi: 10.1002/art.30455.
• [10] 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.
• [11] 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.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [23] 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.
• [24] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.