Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4WYQM2)

• DOT Name: Homeodomain-interacting protein kinase 3 (HIPK3)
• Synonyms: EC 2.7.11.1; Androgen receptor-interacting nuclear protein kinase; ANPK; Fas-interacting serine/threonine-protein kinase; FIST; Homolog of protein kinase YAK1
• Gene Name: HIPK3
• Related Disease:
  Lung cancer
  Lung carcinoma
  Advanced cancer
  Cardiac failure
  Colorectal carcinoma
  Congestive heart failure
  Glioma
  Huntington disease
  Prostate neoplasm
  T-cell leukaemia
  Non-small-cell lung cancer
  Bone osteosarcoma
  Gallbladder cancer
  Gallbladder carcinoma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Non-insulin dependent diabetes
  Osteosarcoma
  Type-1/2 diabetes
• UniProt ID: HIPK3_HUMAN
• PDB ID: 7O7I; 7O7J
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MASQVLVYPPYVYQTQSSAFCSVKKLKVEPSSCVFQERNYPRTYVNGRNFGNSHPPTKGS
  AFQTKIPFNRPRGHNFSLQTSAVVLKNTAGATKVIAAQAQQAHVQAPQIGAWRNRLHFLE
  GPQRCGLKRKSEELDNHSSAMQIVDELSILPAMLQTNMGNPVTVVTATTGSKQNCTTGEG
  DYQLVQHEVLCSMKNTYEVLDFLGRGTFGQVVKCWKRGTNEIVAIKILKNHPSYARQGQI
  EVSILARLSTENADEYNFVRAYECFQHRNHTCLVFEMLEQNLYDFLKQNKFSPLPLKVIR
  PILQQVATALKKLKSLGLIHADLKPENIMLVDPVRQPYRVKVIDFGSASHVSKTVCSTYL
  QSRYYRAPEIILGLPFCEAIDMWSLGCVIAELFLGWPLYPGALEYDQIRYISQTQGLPGE
  QLLNVGTKSTRFFCKETDMSHSGWRLKTLEEHEAETGMKSKEARKYIFNSLDDVAHVNTV
  MDLEGSDLLAEKADRREFVSLLKKMLLIDADLRITPAETLNHPFVNMKHLLDFPHSNHVK
  SCFHIMDICKSHLNSCDTNNHNKTSLLRPVASSSTATLTANFTKIGTLRSQALTTSAHSV
  VHHGIPLQAGTAQFGCGDAFQQTLIICPPAIQGIPATHGKPTSYSIRVDNTVPLVTQAPA
  VQPLQIRPGVLSQTWSGRTQQMLVPAWQQVTPLAPATTTLTSESVAGSHRLGDWGKMISC
  SNHYNSVMPQPLLTNQITLSAPQPVSVGIAHVVWPQPATTKKNKQCQNRGILVKLMEWEP
  GREEINAFSWSNSLQNTNIPHSAFISPKIINGKDVEEVSCIETQDNQNSEGEARNCCETS
  IRQDSDSSVSDKQRQTIIIADSPSPAVSVITISSDTDEEETSQRHSLRECKGSLDCEACQ
  STLNIDRMCSLSSPDSTLSTSSSGQSSPSPCKRPNSMSDEEQESSCDTVDGSPTSDSSGH
  DSPFAESTFVEDTHENTELVSSADTETKPAVCSVVVPPVELENGLNADEHMANTDSICQP
  LIKGRSAPGRLNQPSAVGTRQQKLTSAFQQQHLNFSQVQHFGSGHQEWNGNFGHRRQQAY
  IPTSVTSNPFTLSHGSPNHTAVHAHLAGNTHLGGQPTLLPYPSSATLSSAAPVAHLLASP
  CTSRPMLQHPTYNISHPSGIVHQVPVGLNPRLLPSPTIHQTQYKPIFPPHSYIAASPAYT
  GFPLSPTKLSQYPYM
• Function: Serine/threonine-protein kinase involved in transcription regulation, apoptosis and steroidogenic gene expression. Phosphorylates JUN and RUNX2. Seems to negatively regulate apoptosis by promoting FADD phosphorylation. Enhances androgen receptor-mediated transcription. May act as a transcriptional corepressor for NK homeodomain transcription factors. The phosphorylation of NR5A1 activates SF1 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. In osteoblasts, supports transcription activation: phosphorylates RUNX2 that synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE).
• Tissue Specificity: Overexpressed in multidrug resistant cells. Highly expressed in heart and skeletal muscle, and at lower levels in placenta, pancreas, brain, spleen, prostate, thymus, testis, small intestine, colon and leukocytes. Not found in liver and lung.
• KEGG Pathway: Cellular senescence (hsa04218)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Huntington disease	DISQPLA4	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[7]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Biomarker	[9]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[10]
Gallbladder cancer	DISXJUAF	Limited	Biomarker	[11]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[12]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[13]
Neoplasm	DISZKGEW	Limited	Altered Expression	[13]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[14]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[15]

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 Homeodomain-interacting protein kinase 3 (HIPK3).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Homeodomain-interacting protein kinase 3 (HIPK3).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Homeodomain-interacting protein kinase 3 (HIPK3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Homeodomain-interacting protein kinase 3 (HIPK3).	[27]

References

• [1] Circular RNA HIPK3 exerts oncogenic properties through suppression of miR-124 in lung cancer.Biochem Biophys Res Commun. 2018 Nov 30;506(3):455-462. doi: 10.1016/j.bbrc.2018.10.087. Epub 2018 Oct 20.
• [2] Upregulation of circRNA_0000285 serves as a prognostic biomarker for nasopharyngeal carcinoma and is involved in radiosensitivity.Oncol Lett. 2018 Nov;16(5):6495-6501. doi: 10.3892/ol.2018.9471. Epub 2018 Sep 20.
• [3] Circ-HIPK3 Strengthens the Effects of Adrenaline in Heart Failure by MiR-17-3p - ADCY6 Axis.Int J Biol Sci. 2019 Sep 7;15(11):2484-2496. doi: 10.7150/ijbs.36149. eCollection 2019.
• [4] MiR-382 functions as tumor suppressor and chemosensitizer in colorectal cancer.Biosci Rep. 2019 Aug 9;39(8):BSR20180441. doi: 10.1042/BSR20180441. Print 2019 Aug 30.
• [5] Circular RNA HIPK3 promotes glioma progression by binding to miR-124-3p.Gene. 2019 Mar 30;690:81-89. doi: 10.1016/j.gene.2018.11.073. Epub 2018 Dec 18.
• [6] HIPK3 modulates autophagy and HTT protein levels in neuronal and mouse models of Huntington disease.Autophagy. 2018;14(1):169-170. doi: 10.1080/15548627.2017.1393130. Epub 2018 Jan 29.
• [7] JNK regulates HIPK3 expression and promotes resistance to Fas-mediated apoptosis in DU 145 prostate carcinoma cells.J Biol Chem. 2004 Apr 23;279(17):17090-100. doi: 10.1074/jbc.M307629200. Epub 2004 Feb 6.
• [8] Oncogenic potential of the miR-106-363 cluster and its implication in human T-cell leukemia.Cancer Res. 2007 Jun 15;67(12):5699-707. doi: 10.1158/0008-5472.CAN-06-4478.
• [9] Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPK signaling in STK11 mutant lung cancer.Autophagy. 2020 Apr;16(4):659-671. doi: 10.1080/15548627.2019.1634945. Epub 2019 Jun 28.
• [10] Circular RNA circ_HIPK3 is down-regulated and suppresses cell proliferation, migration and invasion in osteosarcoma.J Cancer. 2018 Apr 26;9(10):1856-1862. doi: 10.7150/jca.24619. eCollection 2018.
• [11] Circular RNA HIPK3 promotes gallbladder cancer cell growth by sponging microRNA-124.Biochem Biophys Res Commun. 2018 Sep 5;503(2):863-869. doi: 10.1016/j.bbrc.2018.06.088. Epub 2018 Aug 2.
• [12] Tudor-staphylococcal nuclease regulates the expression and biological function of alkylglycerone phosphate synthase via nuclear factor-B and microRNA-127 in human glioma U87MG cells.Oncol Lett. 2018 Jun;15(6):9553-9558. doi: 10.3892/ol.2018.8484. Epub 2018 Apr 13.
• [13] The expression level and prognostic value of HIPK3 among non-small-cell lung cancer patients in China.Onco Targets Ther. 2018 Oct 25;11:7459-7469. doi: 10.2147/OTT.S166878. eCollection 2018.
• [14] Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion.Diabetologia. 2014 Jan;57(1):122-8. doi: 10.1007/s00125-013-3089-4. Epub 2013 Oct 23.
• [15] Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus.Circulation. 2017 Oct 24;136(17):1629-1642. doi: 10.1161/CIRCULATIONAHA.117.029004. Epub 2017 Aug 31.
• [16] 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.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] 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.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [25] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [26] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.