Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFOCDD6)

• DOT Name: Heat shock 70 kDa protein 12A (HSPA12A)
• Gene Name: HSPA12A
• Related Disease:
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Drug dependence
  Fatty liver disease
  Gastric cancer
  Hepatocellular carcinoma
  Hyperglycemia
  Liver cirrhosis
  Non-alcoholic steatohepatitis
  Schizophrenia
  Stomach cancer
  Substance abuse
  Substance dependence
  Obesity
  Stroke
• UniProt ID: HS12A_HUMAN
• Sequence:
  MADKEAGGSDGPRETAPTSAYSSPARSLGDTGITPLSPSHIVNDTDSNVSEQQSFLVVVA
  VDFGTTSSGYAYSFTKEPECIHVMRRWEGGDPGVSNQKTPTTILLTPERKFHSFGYAARD
  FYHDLDPNEAKQWLYLEKFKMKLHTTGDLTMDTDLTAANGKKVKALEIFAYALQYFKEQA
  LKELSDQAGSEFENSDVRWVITVPAIWKQPAKQFMRQAAYQAGLASPENSEQLIIALEPE
  AASIYCRKLRLHQMIELSSKAAVNGYSGSDTVGAGFTQAKEHIRRNRQSRTFLVENVIGE
  IWSELEEGDKYVVVDSGGGTVDLTVHQIRLPEGHLKELYKATGGPYGSLGVDYEFEKLLY
  KIFGEDFIEQFKIKRPAAWVDLMIAFESRKRAAAPDRTNPLNITLPFSFIDYYKKFRGHS
  VEHALRKSNVDFVKWSSQGMLRMSPDAMNALFKPTIDSIIEHLRDLFQKPEVSTVKFLFL
  VGGFAEAPLLQQAVQAAFGDQCRIIIPQDVGLTILKGAVLFGLDPAVIKVRRSPLTYGVG
  VLNRYVEGKHPPEKLLVKDGTRWCTDVFDKFISADQSVALGELVKRSYTPAKPSQLVIVI
  NIYSSEHDNVSFITDPGVKKCGTLRLDLTGTSGTAVPARREIQTLMQFGDTEIKATAIDI
  ATSKSVKVGIDFLNY
• Function: Adapter protein for SORL1, but not SORT1. Delays SORL1 internalization and affects SORL1 subcellular localization.
• Tissue Specificity: Widely expressed with highest levels in brain, kidney and muscle.
• Reactome Pathway: Regulation of HSF1-mediated heat shock response (R-HSA-3371453)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Genetic Variation	[1]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[1]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[1]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[1]
Drug dependence	DIS9IXRC	Strong	Biomarker	[3]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[6]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[5]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[7]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[2]
Substance abuse	DIS327VW	Strong	Biomarker	[3]
Substance dependence	DISDRAAR	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Limited	Biomarker	[8]
Stroke	DISX6UHX	Limited	Biomarker	[9]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Indomethacin	DMSC4A7	Approved	Heat shock 70 kDa protein 12A (HSPA12A) increases the Metabolic disorder ADR of Indomethacin.	[29]
Zalcitabine	DMH7MUV	Approved	Heat shock 70 kDa protein 12A (HSPA12A) increases the Cardiotoxicity ADR of Zalcitabine.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[17]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[27]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Heat shock 70 kDa protein 12A (HSPA12A).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Heat shock 70 kDa protein 12A (HSPA12A).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Heat shock 70 kDa protein 12A (HSPA12A).	[26]

References

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• [2] Polymorphisms of PRLHR and HSPA12A and risk of gastric and colorectal cancer in the Chinese Han population.BMC Gastroenterol. 2015 Aug 25;15:107. doi: 10.1186/s12876-015-0336-9.
• [3] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [4] HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization.Diabetes. 2019 Feb;68(2):361-376. doi: 10.2337/db18-0035. Epub 2018 Nov 19.
• [5] Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma.Int J Med Sci. 2015 Feb 15;12(3):256-63. doi: 10.7150/ijms.10735. eCollection 2015.
• [6] HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPAR.Cell Death Differ. 2019 Nov;26(11):2253-2267. doi: 10.1038/s41418-019-0300-2. Epub 2019 Feb 11.
• [7] Heat shock protein 12A shows reduced expression in the prefrontal cortex of subjects with schizophrenia.Biol Psychiatry. 2004 Dec 15;56(12):943-50. doi: 10.1016/j.biopsych.2004.09.005.
• [8] Deficiency of heat shock protein A12A promotes browning of white adipose tissues in mice.Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1451-1459. doi: 10.1016/j.bbadis.2019.02.017. Epub 2019 Feb 22.
• [9] Heat shock protein A12A encodes a novel prosurvival pathway during ischaemic stroke.Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1862-1872. doi: 10.1016/j.bbadis.2018.03.006. Epub 2018 Mar 10.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [18] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [19] 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.
• [20] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [21] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.
• [27] 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.
• [28] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [29] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.