Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUOMBE7)

• DOT Name: SWI/SNF complex subunit SMARCC1 (SMARCC1)
• Synonyms: BRG1-associated factor 155; BAF155; SWI/SNF complex 155 kDa subunit; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 1
• Gene Name: SMARCC1
• Related Disease:
  SMARCC1-associated developmental dysgenesis syndrome
  Acquired aplastic anemia
  Acute myelogenous leukaemia
  Adenocarcinoma
  Endometriosis
  Gastric cancer
  Hepatitis B virus infection
  Hydrocephalus, congenital, 5, susceptibility to
  Lung adenocarcinoma
  Lung cancer
  Lung neoplasm
  Malignant mesothelioma
  Neoplasm
  Neural tube defect
  Pancreatic cancer
  Prostate neoplasm
  Small-cell lung cancer
  Stomach cancer
  Advanced cancer
  Breast cancer
  Breast carcinoma
• UniProt ID: SMRC1_HUMAN
• PDB ID: 2YUS; 5GJK; 6KZ7; 6YXO; 6YXP
• Pfam ID: PF00249 ; PF04433 ; PF16495 ; PF16496 ; PF16498
• Sequence:
  MAAAAGGGGPGTAVGATGSGIAAAAAGLAVYRRKDGGPATKFWESPETVSQLDSVRVWLG
  KHYKKYVHADAPTNKTLAGLVVQLLQFQEDAFGKHVTNPAFTKLPAKCFMDFKAGGALCH
  ILGAAYKYKNEQGWRRFDLQNPSRMDRNVEMFMNIEKTLVQNNCLTRPNIYLIPDIDLKL
  ANKLKDIIKRHQGTFTDEKSKASHHIYPYSSSQDDEEWLRPVMRKEKQVLVHWGFYPDSY
  DTWVHSNDVDAEIEDPPIPEKPWKVHVKWILDTDIFNEWMNEEDYEVDENRKPVSFRQRI
  STKNEEPVRSPERRDRKASANARKRKHSPSPPPPTPTESRKKSGKKGQASLYGKRRSQKE
  EDEQEDLTKDMEDPTPVPNIEEVVLPKNVNLKKDSENTPVKGGTVADLDEQDEETVTAGG
  KEDEDPAKGDQSRSVDLGEDNVTEQTNHIIIPSYASWFDYNCIHVIERRALPEFFNGKNK
  SKTPEIYLAYRNFMIDTYRLNPQEYLTSTACRRNLTGDVCAVMRVHAFLEQWGLVNYQVD
  PESRPMAMGPPPTPHFNVLADTPSGLVPLHLRSPQVPAAQQMLNFPEKNKEKPVDLQNFG
  LRTDIYSKKTLAKSKGASAGREWTEQETLLLLEALEMYKDDWNKVSEHVGSRTQDECILH
  FLRLPIEDPYLENSDASLGPLAYQPVPFSQSGNPVMSTVAFLASVVDPRVASAAAKAALE
  EFSRVREEVPLELVEAHVKKVQEAARASGKVDPTYGLESSCIAGTGPDEPEKLEGAEEEK
  MEADPDGQQPEKAENKVENETDEGDKAQDGENEKNSEKEQDSEVSEDTKSEEKETEENKE
  LTDTCKERESDTGKKKVEHEISEGNVATAAAAALASAATKAKHLAAVEERKIKSLVALLV
  ETQMKKLEIKLRHFEELETIMDREKEALEQQRQQLLTERQNFHMEQLKYAELRARQQMEQ
  QQHGQNPQQAHQHSGGPGLAPLGAAGHPGMMPHQQPPPYPLMHHQMPPPHPPQPGQIPGP
  GSMMPGQHMPGRMIPTVAANIHPSGSGPTPPGMPPMPGNILGPRVPLTAPNGMYPPPPQQ
  QPPPPPPADGVPPPPAPGPPASAAP
• Function: Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. May stimulate the ATPase activity of the catalytic subunit of the complex. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth.
• Tissue Specificity: Expressed in brain, heart, muscle, placenta, lung, liver, muscle, kidney and pancreas.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Thermogenesis (hsa04714)
  Hepatocellular carcinoma (hsa05225)
• Reactome Pathway:
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  RMTs methylate histone arginines (R-HSA-3214858)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
SMARCC1-associated developmental dysgenesis syndrome	DIS9UTNR	Definitive	Autosomal dominant	[1]
Acquired aplastic anemia	DISCMKMX	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[4]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[7]
Hydrocephalus, congenital, 5, susceptibility to	DIST33T1	Strong	Autosomal dominant	[8]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Malignant mesothelioma	DISTHJGH	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[8]
Pancreatic cancer	DISJC981	Strong	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[13]
Small-cell lung cancer	DISK3LZD	Strong	Genetic Variation	[5]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[14]
Breast cancer	DIS7DPX1	Limited	Biomarker	[15]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[15]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	SWI/SNF complex subunit SMARCC1 (SMARCC1) increases the response to substance of Arsenic trioxide.	[27]

12 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 SWI/SNF complex subunit SMARCC1 (SMARCC1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[20]
Selenium	DM25CGV	Approved	Selenium decreases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[21]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[22]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[23]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[25]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of SWI/SNF complex subunit SMARCC1 (SMARCC1).	[24]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] SWI/SNF subunit expression heterogeneity in human aplastic anemia stem/progenitors.Exp Hematol. 2018 Jun;62:39-44.e2. doi: 10.1016/j.exphem.2018.03.005. Epub 2018 Mar 27.
• [3] SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia.Mol Cancer Res. 2018 May;16(5):791-804. doi: 10.1158/1541-7786.MCR-17-0493. Epub 2018 Feb 26.
• [4] Varied pathways of stage IA lung adenocarcinomas discovered by integrated gene expression analysis.Int J Biol Sci. 2011 Apr 28;7(5):551-66. doi: 10.7150/ijbs.7.551.
• [5] SWI/SNF Complexes in Ovarian Cancer: Mechanistic Insights and Therapeutic Implications.Mol Cancer Res. 2018 Dec;16(12):1819-1825. doi: 10.1158/1541-7786.MCR-18-0368. Epub 2018 Jul 23.
• [6] Genome-wide analysis of histone modifications by ChIP-chip to identify silenced genes in gastric cancer.Oncol Rep. 2015 May;33(5):2567-74. doi: 10.3892/or.2015.3824. Epub 2015 Feb 27.
• [7] Chromatin remodelling factor BAF155 protects hepatitis B virus X protein (HBx) from ubiquitin-independent proteasomal degradation.Emerg Microbes Infect. 2019;8(1):1393-1405. doi: 10.1080/22221751.2019.1666661.
• [8] A mendelian form of neural tube defect caused by a de novo null variant in SMARCC1 in an identical twin. Ann Neurol. 2018 Feb;83(2):433-436. doi: 10.1002/ana.25152. Epub 2018 Feb 9.
• [9] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [10] High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma.Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13432-13437. doi: 10.1073/pnas.1612074113. Epub 2016 Nov 9.
• [11] CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity.Nat Commun. 2018 Feb 12;9(1):631. doi: 10.1038/s41467-018-03031-3.
• [12] miR-320c regulates gemcitabine-resistance in pancreatic cancer via SMARCC1.Br J Cancer. 2013 Jul 23;109(2):502-11. doi: 10.1038/bjc.2013.320. Epub 2013 Jun 25.
• [13] SMARCC1 expression is upregulated in prostate cancer and positively correlated with tumour recurrence and dedifferentiation.Histol Histopathol. 2008 Sep;23(9):1069-76. doi: 10.14670/HH-23.1069.
• [14] Modeling cancer driver events in vitro using barrier bypass-clonal expansion assays and massively parallel sequencing.Oncogene. 2017 Oct 26;36(43):6041-6048. doi: 10.1038/onc.2017.215. Epub 2017 Jul 10.
• [15] CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis.Cancer Cell. 2014 Jan 13;25(1):21-36. doi: 10.1016/j.ccr.2013.12.007.
• [16] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [17] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [18] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [19] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [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] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] Fulvestrant induces resistance by modulating GPER and CDK6 expression: implication of methyltransferases, deacetylases and the hSWI/SNF chromatin remodelling complex. Br J Cancer. 2013 Nov 12;109(10):2751-62. doi: 10.1038/bjc.2013.583. Epub 2013 Oct 29.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] 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.
• [25] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [26] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [27] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.