Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD3MYS0)

• DOT Name: HEAT repeat-containing protein 6 (HEATR6)
• Synonyms: Amplified in breast cancer protein 1
• Gene Name: HEATR6
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Colorectal carcinoma
  Epithelial ovarian cancer
  Estrogen-receptor positive breast cancer
  Influenza
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Triple negative breast cancer
  Coronary atherosclerosis
  Coronary heart disease
  Neoplasm
  Epithelial neoplasm
  Ductal breast carcinoma in situ
  Glioma
  Lung adenocarcinoma
  Tangier disease
• UniProt ID: HEAT6_HUMAN
• Pfam ID: PF13251
• Sequence:
  MAAVQVVGSWPSVQPREAPREAIPERGNGFRLLSARLCALRPDDSSSARTEIHLLFDQLI
  SENYSEGSGVAPEDVSALLVQACRLVPLNQNHLVSKVSQLIHHLLNRLQVIVDEQHLDFL
  LAYTISAIHQCSSWTHREILQALAALVYCNGSKCQKYLPELLGNTGLLMKLSDLAQSDPE
  VRRAAVHCMANLCLSVPGQPYLEEPYQNVCFQAFLTILQSPKSSDMDDITFCMLLQNALK
  GIQSLLNGGRMKLTQTDELGALLAVLKKFMFHGLPGLNIEMPTVLYPTPLPQYDGRTPIK
  PQQSESSASRPTLNKKKKSKVKPKKIQQGEEEEKESSGEIEAAPVTGTGRVNLHEGNTWC
  PSSLGVQSLPLDGSGAAEKDGVSSSFSSSSWKRVSSSESDFSDAEGGMQSKMRSYQAKVR
  QGALVCFLSTIKSIEKKVLYGYWSAFIPDTPELGSPQSVSLMTLTLKDPSPKTRACALQV
  LSAILEGSKQFLSVAEDTSDHRRAFTPFSVMIACSIRELHRCLLLALVAESSSQTVTQII
  KCLANLVSNAPYDRLKLSLLTKVWNQIKPYIRHKDVNVRVSSLTLLGAIVSTHAPLPEVQ
  LLLQQPCSSGLGNSNSATPHLSPPDWWKKAPAGPSLEETSVSSPKGSSEPCWLIRLCISI
  VVLPKEDSCSGSDAGSAAGSTYEPSPMRLEALQVLTLLARGYFSMTQAYLMELGEVICKC
  MGEADPSIQLHGAKLLEELGTGLIQQYKPDSTAAPDQRAPVFLVVMFWTMMLNGPLPRAL
  QNSEHPTLQASACDALSSILPEAFSNLPNDRQMLCITVLLGLNDSKNRLVKAATSRALGV
  YVLFPCLRQDVIFVADAANAILMSLEDKSLNVRAKAAWSLGNLTDTLIVNMETPDPSFQE
  EFSGLLLLKMLRSAIEASKDKDKVKSNAVRALGNLLHFLQPSHIEKPTFAEIIEESIQAL
  ISTVLTEAAMKVRWNACYAMGNVFKNPALPLGTAPWTSQAYNALTSVVTSCKNFKVRIRS
  AAALSVPGKREQYGSVDQYARIWNALVTALQKSEDTIDFLEFKYCVSLRTQICQALIHLL
  SLASASDLPCMKETLELSGNMVQSYILQFLKSGAEGDDTGAPHSPQERDQMVRMALKHMG
  SIQAPTGDTARRAIMGFLEEILAVCFDSSGSQGALPGLTNQ
• Function: Amplification-dependent oncogene.
• Tissue Specificity: Amplified in breast cancer cell lines MCF-7 and BT-474.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[6]
Influenza	DIS3PNU3	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[9]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[10]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[10]
Neoplasm	DISZKGEW	moderate	Biomarker	[9]
Epithelial neoplasm	DIS0T594	Disputed	Biomarker	[11]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Altered Expression	[12]
Glioma	DIS5RPEH	Limited	Biomarker	[13]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[14]
Tangier disease	DIS57P0M	Limited	Genetic Variation	[15]

8 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 repeat-containing protein 6 (HEATR6).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of HEAT repeat-containing protein 6 (HEATR6).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of HEAT repeat-containing protein 6 (HEATR6).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of HEAT repeat-containing protein 6 (HEATR6).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of HEAT repeat-containing protein 6 (HEATR6).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of HEAT repeat-containing protein 6 (HEATR6).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of HEAT repeat-containing protein 6 (HEATR6).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of HEAT repeat-containing protein 6 (HEATR6).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of HEAT repeat-containing protein 6 (HEATR6).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of HEAT repeat-containing protein 6 (HEATR6).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of HEAT repeat-containing protein 6 (HEATR6).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of HEAT repeat-containing protein 6 (HEATR6).	[21]

References

• [1] AIB1 predicts tumor response to definitive chemoradiotherapy and prognosis in cervical squamous cell carcinoma.J Cancer. 2019 Aug 28;10(21):5212-5222. doi: 10.7150/jca.31697. eCollection 2019.
• [2] Concise approach for screening long non-coding RNAs functionally linked to human breast cancer associated genes.Exp Mol Pathol. 2019 Jun;108:89-96. doi: 10.1016/j.yexmp.2019.04.003. Epub 2019 Apr 3.
• [3] The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.Nat Genet. 1999 Aug;22(4):347-51. doi: 10.1038/11914.
• [4] Amplified in breast cancer 1 promotes colorectal cancer progression through enhancing notch signaling.Oncogene. 2015 Jul 23;34(30):3935-3945. doi: 10.1038/onc.2014.324. Epub 2014 Sep 29.
• [5] AIB1 regulates the ovarian cancer cell cycle through TUG1.Eur Rev Med Pharmacol Sci. 2017 Dec;21(24):5610-5617. doi: 10.26355/eurrev_201712_14002.
• [6] Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer: the Danish cohort of BIG 1-98.Breast Cancer Res Treat. 2017 Nov;166(2):481-490. doi: 10.1007/s10549-017-4416-0. Epub 2017 Aug 1.
• [7] Down-regulation of the expression of O-acetyl-GD3 by the O-acetylesterase cDNA in hamster melanoma cells: effects on cellular proliferation, differentiation, and melanogenesis.J Neurochem. 1999 Mar;72(3):954-61. doi: 10.1046/j.1471-4159.1999.0720954.x.
• [8] Overexpression of AIB1 negatively affects survival of surgically resected non-small-cell lung cancer patients.Ann Oncol. 2010 Aug;21(8):1675-1681. doi: 10.1093/annonc/mdp592. Epub 2010 Jan 11.
• [9] Depletion of the Transcriptional Coactivator Amplified in Breast Cancer 1 (AIB1) Uncovers Functionally Distinct Subpopulations in Triple-Negative Breast Cancer.Neoplasia. 2019 Oct;21(10):963-973. doi: 10.1016/j.neo.2019.07.001. Epub 2019 Aug 19.
• [10] A point mutation in ABC1 gene in a patient with severe premature coronary heart disease and mild clinical phenotype of Tangier disease.Atherosclerosis. 2001 Feb 15;154(3):599-605. doi: 10.1016/s0021-9150(00)00587-6.
• [11] Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells.Mol Cell Biol. 2008 Nov;28(21):6580-93. doi: 10.1128/MCB.00118-08. Epub 2008 Sep 2.
• [12] The nuclear coactivator amplified in breast cancer 1 maintains tumor-initiating cells during development of ductal carcinoma in situ.Oncogene. 2014 Jun 5;33(23):3033-42. doi: 10.1038/onc.2013.263. Epub 2013 Jul 15.
• [13] Identification of genes that modulate sensitivity of U373MG glioblastoma cells to cis-platinum.Anticancer Drugs. 2006 Aug;17(7):733-51. doi: 10.1097/01.cad.0000217429.67455.18.
• [14] Overexpression of amplified in breast cancer 1 (AIB1) gene promotes lung adenocarcinoma aggressiveness in vitro and in vivo by upregulating C-X-C motif chemokine receptor 4.Cancer Commun (Lond). 2018 Aug 13;38(1):53. doi: 10.1186/s40880-018-0320-1.
• [15] A novel nonsense mutation in the ABC1 gene causes a severe syringomyelia-like phenotype of Tangier disease.Brain. 2003 Apr;126(Pt 4):920-7. doi: 10.1093/brain/awg074.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [24] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.