Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1UX9SK)

• DOT Name: Heat shock factor protein 4 (HSF4)
• Synonyms: HSF 4; hHSF4; Heat shock transcription factor 4; HSTF 4
• Gene Name: HSF4
• Related Disease:
  Cataract 5 multiple types
  Cataract
  Colorectal carcinoma
  Early-onset posterior polar cataract
  Hepatitis B virus infection
  Hepatitis C virus infection
  Liver cirrhosis
  Cardiovascular disease
  Early-onset lamellar cataract
  Total early-onset cataract
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: HSF4_HUMAN
• PDB ID: 6J6V; 6J6W
• Pfam ID: PF00447
• Sequence:
  MQEAPAALPTEPGPSPVPAFLGKLWALVGDPGTDHLIRWSPSGTSFLVSDQSRFAKEVLP
  QYFKHSNMASFVRQLNMYGFRKVVSIEQGGLLRPERDHVEFQHPSFVRGREQLLERVRRK
  VPALRGDDGRWRPEDLGRLLGEVQALRGVQESTEARLRELRQQNEILWREVVTLRQSHGQ
  QHRVIGKLIQCLFGPLQAGPSNAGGKRKLSLMLDEGSSCPTPAKFNTCPLPGALLQDPYF
  IQSPLPETNLGLSPHRARGPIISDIPEDSPSPEGTRLSPSSDGRREKGLALLKEEPASPG
  GDGEAGLALAPNECDFCVTAPPPLPVAVVQAILEGKGSFSPEGPRNAQQPEPGDPREIPD
  RGPLGLESGDRSPESLLPPMLLQPPQESVEPAGPLDVLGPSLQGREWTLMDLDMELSLMQ
  PLVPERGEPELAVKGLNSPSPGKDPTLGAPLLLDVQAALGGPALGLPGALTIYSTPESRT
  ASYLGPEASPSP
• Function: Heat-shock transcription factor that specifically binds heat shock promoter elements (HSE). Required for denucleation and organelle rupture and degradation that occur during eye lens terminal differentiation, when fiber cells that compose the lens degrade all membrane-bound organelles in order to provide lens with transparency to allow the passage of light. In this process, may regulate denucleation of lens fiber cells in part by activating DNASE2B transcription. May be involved in DNA repair through the transcriptional regulation of RAD51. May up-regulate p53/TP53 protein in eye lens fiber cells, possibly through protein stabilization. In the eye lens, controls the expression of alpha-crystallin B chain/CRYAB and consequently may be involved in the regulation of lysosomal acidification; [Isoform HSF4A]: Transcriptional repressor; [Isoform HSF4B]: Transcriptional activator.
• Tissue Specificity: Expressed in heart, skeletal muscle, eye and brain, and at much lower levels in some other tissues.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract 5 multiple types	DIS4AZEB	Definitive	Autosomal recessive	[1]
Cataract	DISUD7SL	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Early-onset posterior polar cataract	DISJFK9W	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[7]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[8]
Early-onset lamellar cataract	DISR7WXX	Supportive	Autosomal dominant	[9]
Total early-onset cataract	DISACMEZ	Supportive	Autosomal dominant	[10]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[11]
Lung cancer	DISCM4YA	Limited	Biomarker	[12]
Lung carcinoma	DISTR26C	Limited	Biomarker	[12]

2 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 Heat shock factor protein 4 (HSF4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Heat shock factor protein 4 (HSF4).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Heat shock factor protein 4 (HSF4).	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Heat shock factor protein 4 (HSF4).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Heat shock factor protein 4 (HSF4).	[16]

References

• [1] Novel mutations in HSF4 cause congenital cataracts in Chinese families. BMC Med Genet. 2018 Aug 24;19(1):150. doi: 10.1186/s12881-018-0636-3.
• [2] Novel mutations identified in Chinese families with autosomal dominant congenital cataracts by targeted next-generation sequencing.BMC Med Genet. 2019 Dec 16;20(1):196. doi: 10.1186/s12881-019-0933-5.
• [3] High HSF4 expression is an independent indicator of poor overall survival and recurrence free survival in patients with primary colorectal cancer.IUBMB Life. 2017 Dec;69(12):956-961. doi: 10.1002/iub.1692. Epub 2017 Nov 13.
• [4] Copy number variations of DNA repair genes and the age-related cataract: Jiangsu Eye Study.Invest Ophthalmol Vis Sci. 2013 Feb 1;54(2):932-8. doi: 10.1167/iovs.12-10948.
• [5] A multi-center clinical study comparing Sansure Magb and CAP/CTM HBV tests in the quantitative detection of HBV DNA.J Infect Dev Ctries. 2016 Aug 2;10(7):755-61. doi: 10.3855/jidc.7112.
• [6] Diagnosis and monitoring of HCV infection using the cobas() HCV test for use on the cobas() 6800/8800 systems.J Clin Virol. 2018 May;102:63-69. doi: 10.1016/j.jcv.2018.02.017. Epub 2018 Feb 24.
• [7] Comparison of the Abbott RealTime HCV and Roche COBAS Ampliprep/COBAS TaqMan HCV assays for the monitoring of sofosbuvir-based therapy.Antivir Ther. 2017;22(1):61-70. doi: 10.3851/IMP3085. Epub 2016 Sep 15.
• [8] Novel Ce(III)-Metal Organic Framework with a Luminescent Property To Fabricate an Electrochemiluminescence Immunosensor.ACS Appl Mater Interfaces. 2020 Jan 8;12(1):338-346. doi: 10.1021/acsami.9b19246. Epub 2019 Dec 27.
• [9] Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nat Genet. 2002 Jul;31(3):276-8. doi: 10.1038/ng921. Epub 2002 Jun 24.
• [10] A homozygous splice mutation in the HSF4 gene is associated with an autosomal recessive congenital cataract. Invest Ophthalmol Vis Sci. 2004 Aug;45(8):2716-21. doi: 10.1167/iovs.03-1370.
• [11] Quantified postsurgical small cell size CTCs and EpCAM(+) circulating tumor stem cells with cytogenetic abnormalities in hepatocellular carcinoma patients determine cancer relapse.Cancer Lett. 2018 Jan 1;412:99-107. doi: 10.1016/j.canlet.2017.10.004. Epub 2017 Oct 13.
• [12] Targeted blockade of TGF- and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts.Sci Rep. 2017 Aug 17;7(1):8660. doi: 10.1038/s41598-017-09020-8.
• [13] 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.
• [14] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [17] 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.