Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY7IER8)

• DOT Name: Class A basic helix-loop-helix protein 15 (BHLHA15)
• Synonyms: bHLHa15; Class B basic helix-loop-helix protein 8; bHLHb8; Muscle, intestine and stomach expression 1; MIST-1
• Gene Name: BHLHA15
• Related Disease:
  Breast cancer
  Breast carcinoma
  Keratoconjunctivitis sicca
  Mammary analogue secretory carcinoma
  Matthew-Wood syndrome
  Pancreatic tumour
  Plasma cell myeloma
  Plasma cell neoplasm
  Gastric cancer
  Pancreatic cancer
  Stomach cancer
  Advanced cancer
  Autoimmune polyendocrinopathy
  Chronic pancreatitis
• UniProt ID: BHA15_HUMAN
• Pfam ID: PF00010
• Sequence:
  MKTKNRPPRRRAPVQDTEATPGEGTPDGSLPNPGPEPAKGLRSRPARAAARAPGEGRRRR
  PGPSGPGGRRDSSIQRRLESNERERQRMHKLNNAFQALREVIPHVRADKKLSKIETLTLA
  KNYIKSLTATILTMSSSRLPGLEGPGPKLYQHYQQQQQVAGGALGATEAQPQGHLQRYST
  QIHSFREGT
• Function: Plays a role in controlling the transcriptional activity of MYOD1, ensuring that expanding myoblast populations remain undifferentiated. Repression may occur through muscle-specific E-box occupancy by homodimers. May also negatively regulate bHLH-mediated transcription through an N-terminal repressor domain. Serves as a key regulator of acinar cell function, stability, and identity. Also required for normal organelle localization in exocrine cells and for mitochondrial calcium ion transport. May function as a unique regulator of gene expression in several different embryonic and postnatal cell lineages. Binds to the E-box consensus sequence 5'-CANNTG-3'.
• Tissue Specificity: Expressed in brain, liver, spleen and skeletal muscle.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Keratoconjunctivitis sicca	DISNOENH	Strong	Biomarker	[2]
Mammary analogue secretory carcinoma	DISGXZ2Q	Strong	Altered Expression	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[4]
Pancreatic tumour	DIS3U0LK	Strong	Genetic Variation	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[6]
Plasma cell neoplasm	DIS2PJJM	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[7]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[8]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Autoimmune polyendocrinopathy	DISOLDB2	Limited	Altered Expression	[10]
Chronic pancreatitis	DISBUOMJ	Limited	Biomarker	[11]

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 Class A basic helix-loop-helix protein 15 (BHLHA15).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Class A basic helix-loop-helix protein 15 (BHLHA15).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Class A basic helix-loop-helix protein 15 (BHLHA15).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Class A basic helix-loop-helix protein 15 (BHLHA15).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Class A basic helix-loop-helix protein 15 (BHLHA15).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Class A basic helix-loop-helix protein 15 (BHLHA15).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Class A basic helix-loop-helix protein 15 (BHLHA15).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Class A basic helix-loop-helix protein 15 (BHLHA15).	[18]

References

• [1] Differential gene expression pattern in human mammary epithelial cells induced by realistic organochlorine mixtures described in healthy women and in women diagnosed with breast cancer.Toxicol Lett. 2016 Mar 30;246:42-8. doi: 10.1016/j.toxlet.2016.02.003. Epub 2016 Feb 4.
• [2] Aire-deficient mice provide a model of corneal and lacrimal gland neuropathy in Sjgren's syndrome.PLoS One. 2017 Sep 19;12(9):e0184916. doi: 10.1371/journal.pone.0184916. eCollection 2017.
• [3] Mist1: a novel nuclear marker for acinic cell carcinoma of the salivary gland.Virchows Arch. 2019 Nov;475(5):617-624. doi: 10.1007/s00428-019-02600-1. Epub 2019 Jun 11.
• [4] Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment.Mol Oncol. 2018 Jun;12(7):1104-1124. doi: 10.1002/1878-0261.12314. Epub 2018 May 21.
• [5] p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells.Oncogene. 2016 Aug 11;35(32):4282-8. doi: 10.1038/onc.2015.441. Epub 2015 Nov 23.
• [6] Transcription factor MIST1 in terminal differentiation of mouse and human plasma cells.Physiol Genomics. 2011 Feb 11;43(3):174-86. doi: 10.1152/physiolgenomics.00084.2010. Epub 2010 Nov 23.
• [7] The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner.Lab Invest. 2013 Jan;93(1):112-22. doi: 10.1038/labinvest.2012.131. Epub 2012 Oct 29.
• [8] Overexpression of MIST1 reverses the epithelial-mesenchymal transition and reduces the tumorigenicity of pancreatic cancer cells via the Snail/E-cadherin pathway.Cancer Lett. 2018 Sep 1;431:96-104. doi: 10.1016/j.canlet.2018.05.043. Epub 2018 May 31.
• [9] Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche.Cancer Cell. 2015 Dec 14;28(6):800-814. doi: 10.1016/j.ccell.2015.10.003. Epub 2015 Nov 12.
• [10] Gastric adenocarcinoma of the fundic gland type shares common genetic and phenotypic features with pyloric gland adenoma.Pathol Int. 2013 Jun;63(6):318-25. doi: 10.1111/pin.12070.
• [11] Activation of protein kinase C leads to increased pancreatic acinar cell dedifferentiation in the absence of MIST1.J Pathol. 2012 Nov;228(3):351-65. doi: 10.1002/path.4015. Epub 2012 May 2.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.