Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWO5SCF)

• DOT Name: Transcription cofactor HES-6 (HES6)
• Synonyms: C-HAIRY1; Class B basic helix-loop-helix protein 41; bHLHb41; Hairy and enhancer of split 6
• Gene Name: HES6
• Related Disease:
  Advanced cancer
  Astrocytoma
  Bone disease
  Breast neoplasm
  Colon carcinoma
  Colorectal carcinoma
  Glioma
  Hepatocellular carcinoma
  Immunodeficiency
  Liver cirrhosis
  Metastatic malignant neoplasm
  Neoplasm
  Plasma cell myeloma
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Mood disorder
  Rhabdomyosarcoma
  Breast cancer
  Breast carcinoma
  Castration-resistant prostate carcinoma
• UniProt ID: HES6_HUMAN
• Pfam ID: PF07527 ; PF00010
• Sequence:
  MAPPAAPGRDRVGREDEDGWETRGDRKARKPLVEKKRRARINESLQELRLLLAGAEVQAK
  LENAEVLELTVRRVQGVLRGRAREREQLQAEASERFAAGYIQCMHEVHTFVSTCQAIDAT
  VAAELLNHLLESMPLREGSSFQDLLGDALAGPPRAPGRSGWPAGGAPGSPIPSPPGPGDD
  LCSDLEEAPEAELSQAPAEGPDLVPAALGSLTTAQIARSVWRPW
• Function: Does not bind DNA itself but suppresses both HES1-mediated N box-dependent transcriptional repression and binding of HES1 to E box sequences. Also suppresses HES1-mediated inhibition of the heterodimer formed by ASCL1/MASH1 and TCF3/E47, allowing ASCL1 and TCF3 to up-regulate transcription in its presence. Promotes cell differentiation.
• KEGG Pathway: Human papillomavirus infection (hsa05165)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Astrocytoma	DISL3V18	Strong	Altered Expression	[2]
Bone disease	DISE1F82	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Immunodeficiency	DIS093I0	Strong	Biomarker	[4]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[3]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Mood disorder	DISLVMWO	moderate	Genetic Variation	[10]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[11]
Breast cancer	DIS7DPX1	Limited	Biomarker	[1]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[1]
Castration-resistant prostate carcinoma	DISVGAE6	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 Transcription cofactor HES-6 (HES6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription cofactor HES-6 (HES6).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcription cofactor HES-6 (HES6).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcription cofactor HES-6 (HES6).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Transcription cofactor HES-6 (HES6).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transcription cofactor HES-6 (HES6).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transcription cofactor HES-6 (HES6).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription cofactor HES-6 (HES6).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription cofactor HES-6 (HES6).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transcription cofactor HES-6 (HES6).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transcription cofactor HES-6 (HES6).	[22]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Transcription cofactor HES-6 (HES6).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Transcription cofactor HES-6 (HES6).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Transcription cofactor HES-6 (HES6).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcription cofactor HES-6 (HES6).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Transcription cofactor HES-6 (HES6).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transcription cofactor HES-6 (HES6).	[28]

References

• [1] Overexpression of HES6 has prognostic value and promotes metastasis via the Wnt/-catenin signaling pathway in colorectal cancer.Oncol Rep. 2018 Sep;40(3):1261-1274. doi: 10.3892/or.2018.6539. Epub 2018 Jul 2.
• [2] HES6 gene is selectively overexpressed in glioma and represents an important transcriptional regulator of glioma proliferation.Oncogene. 2012 Mar 8;31(10):1299-310. doi: 10.1038/onc.2011.316. Epub 2011 Jul 25.
• [3] Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche.Oncotarget. 2016 Aug 30;7(35):56013-56029. doi: 10.18632/oncotarget.10820.
• [4] Hes-6, an inhibitor of Hes-1, is regulated by 17beta-estradiol and promotes breast cancer cell proliferation.Breast Cancer Res. 2009;11(6):R79. doi: 10.1186/bcr2446. Epub 2009 Nov 5.
• [5] Detection of differentially expressed HES-6 gene in metastatic colon carcinoma by combination of suppression subtractive hybridization and cDNA library array.Cancer Lett. 2003 Aug 20;198(2):229-39. doi: 10.1016/s0304-3835(03)00313-6.
• [6] LncSHRG promotes hepatocellular carcinoma progression by activating HES6.Oncotarget. 2017 Aug 3;8(41):70630-70641. doi: 10.18632/oncotarget.19906. eCollection 2017 Sep 19.
• [7] Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma.Liver Int. 2007 Sep;27(7):997-1007. doi: 10.1111/j.1478-3231.2007.01544.x.
• [8] The Siah2-HIF-FoxA2 axis in prostate cancer ?new markers and therapeutic opportunities.Oncotarget. 2010 Sep;1(5):379-85. doi: 10.18632/oncotarget.171.
• [9] HES6 promotes prostate cancer aggressiveness independently of Notch signalling.J Cell Mol Med. 2015 Jul;19(7):1624-36. doi: 10.1111/jcmm.12537. Epub 2015 Apr 12.
• [10] Expression and association analyses of promoter variants of the neurogenic gene HES6, a candidate gene for mood disorder susceptibility and antidepressant response.Neurosci Lett. 2009 Aug 28;460(2):185-90. doi: 10.1016/j.neulet.2009.05.065. Epub 2009 May 28.
• [11] HES6 enhances the motility of alveolar rhabdomyosarcoma cells.Exp Cell Res. 2013 Jan 1;319(1):103-12. doi: 10.1016/j.yexcr.2012.08.010. Epub 2012 Sep 14.
• [12] HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network.EMBO Mol Med. 2014 May;6(5):651-61. doi: 10.1002/emmm.201303581.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [22] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [23] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [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] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [26] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [27] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [28] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.