Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXNJIJ9)

• DOT Name: Heat shock factor protein 2 (HSF2)
• Synonyms: HSF 2; Heat shock transcription factor 2; HSTF 2
• Gene Name: HSF2
• Related Disease:
  Acute erythroid leukemia
  Atrial fibrillation
  Autosomal recessive bestrophinopathy
  Azoospermia
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Crohn disease
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Male infertility
  Neoplasm
  Thyroid gland carcinoma
  Ulcerative colitis
  Familial atrial fibrillation
  Advanced cancer
  Cardiomyopathy
  Prostate cancer
  Prostate carcinoma
• UniProt ID: HSF2_HUMAN
• PDB ID: 5D8K; 5D8L; 5HDK; 7DCI; 7DCU
• Pfam ID: PF00447 ; PF06546
• Sequence:
  MKQSSNVPAFLSKLWTLVEETHTNEFITWSQNGQSFLVLDEQRFAKEILPKYFKHNNMAS
  FVRQLNMYGFRKVVHIDSGIVKQERDGPVEFQHPYFKQGQDDLLENIKRKVSSSKPEENK
  IRQEDLTKIISSAQKVQIKQETIESRLSELKSENESLWKEVSELRAKHAQQQQVIRKIVQ
  FIVTLVQNNQLVSLKRKRPLLLNTNGAQKKNLFQHIVKEPTDNHHHKVPHSRTEGLKPRE
  RISDDIIIYDVTDDNADEENIPVIPETNEDVISDPSNCSQYPDIVIVEDDNEDEYAPVIQ
  SGEQNEPARESLSSGSDGSSPLMSSAVQLNGSSSLTSEDPVTMMDSILNDNINLLGKVEL
  LDYLDSIDCSLEDFQAMLSGRQFSIDPDLLVDLFTSSVQMNPTDYINNTKSENKGLETTK
  NNVVQPVSEEGRKSKSKPDKQLIQYTAFPLLAFLDGNPASSVEQASTTASSEVLSSVDKP
  IEVDELLDSSLDPEPTQSKLVRLEPLTEAEASEATLFYLCELAPAPLDSDMPLLDS
• Function: DNA-binding protein that specifically binds heat shock promoter elements (HSE) and activates transcription. In higher eukaryotes, HSF is unable to bind to the HSE unless the cells are heat shocked.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute erythroid leukemia	DISZFC1O	Strong	Biomarker	[1]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[2]
Autosomal recessive bestrophinopathy	DISU5FU5	Strong	Genetic Variation	[3]
Azoospermia	DIS94181	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Male infertility	DISY3YZZ	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[10]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[6]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[13]
Prostate cancer	DISF190Y	Limited	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Heat shock factor protein 2 (HSF2).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Heat shock factor protein 2 (HSF2).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Heat shock factor protein 2 (HSF2).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heat shock factor protein 2 (HSF2).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Heat shock factor protein 2 (HSF2).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Heat shock factor protein 2 (HSF2).	[19]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Heat shock factor protein 2 (HSF2).	[20]
MG-132	DMKA2YS	Preclinical	MG-132 increases the activity of Heat shock factor protein 2 (HSF2).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Heat shock factor protein 2 (HSF2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Heat shock factor protein 2 (HSF2).	[21]

References

• [1] Heat shock factor 2 (HSF2) contributes to inducible expression of hsp genes through interplay with HSF1.J Biol Chem. 2007 Mar 9;282(10):7077-86. doi: 10.1074/jbc.M607556200. Epub 2007 Jan 9.
• [2] RNA sequencing profiling reveals key mRNAs and long noncoding RNAs in atrial fibrillation.J Cell Biochem. 2020 Aug;121(8-9):3752-3763. doi: 10.1002/jcb.29504. Epub 2019 Nov 3.
• [3] Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy.Int J Cardiol. 2018 Apr 15;257:283-290. doi: 10.1016/j.ijcard.2017.10.102. Epub 2017 Nov 10.
• [4] A dominant-negative mutation of HSF2 associated with idiopathic azoospermia.Hum Genet. 2013 Feb;132(2):159-65. doi: 10.1007/s00439-012-1234-7. Epub 2012 Oct 14.
• [5] ALG3 Is Activated by Heat Shock Factor 2 and Promotes Breast Cancer Growth.Med Sci Monit. 2018 May 25;24:3479-3487. doi: 10.12659/MSM.907461.
• [6] Heat shock factor 2 levels are associated with the severity of ulcerative colitis.PLoS One. 2014 Feb 12;9(2):e88822. doi: 10.1371/journal.pone.0088822. eCollection 2014.
• [7] Tumor-associated antigenic pattern in squamous cell carcinomas of the head and neck--analysed by SEREX.Eur J Cancer. 2013 Mar;49(4):e1-7. doi: 10.1016/j.ejca.2005.09.036. Epub 2006 Jul 11.
• [8] HSF2 regulates aerobic glycolysis by suppression of FBP1 in hepatocellular carcinoma.Am J Cancer Res. 2019 Aug 1;9(8):1607-1621. eCollection 2019.
• [9] The Role of Heat Shock Factors in Mammalian Spermatogenesis.Adv Anat Embryol Cell Biol. 2017;222:45-65. doi: 10.1007/978-3-319-51409-3_3.
• [10] E2F, HSF2, and miR-26 in thyroid carcinoma: bioinformatic analysis of RNA-sequencing data.Genet Mol Res. 2016 Mar 11;15(1):15017576. doi: 10.4238/gmr.15017576.
• [11] Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
• [12] Heat-shock factor 2 is a suppressor of prostate cancer invasion.Oncogene. 2016 Apr 7;35(14):1770-84. doi: 10.1038/onc.2015.241. Epub 2015 Jun 29.
• [13] p53-mediated miR-18 repression activates HSF2 for IGF-IIR-dependent myocyte hypertrophy in hypertension-induced heart failure.Cell Death Dis. 2017 Aug 10;8(8):e2990. doi: 10.1038/cddis.2017.320.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] The proteasome inhibitor bortezomib is a potent inducer of zinc finger AN1-type domain 2a gene expression: role of heat shock factor 1 (HSF1)-heat shock factor 2 (HSF2) heterocomplexes. J Biol Chem. 2014 May 2;289(18):12705-15. doi: 10.1074/jbc.M113.513242. Epub 2014 Mar 11.
• [21] 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.
• [22] Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells. Am J Physiol Regul Integr Comp Physiol. 2002 Apr;282(4):R1016-26. doi: 10.1152/ajpregu.00492.2001.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.