Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0EC5BQ)

• DOT Name: Actin-like protein 6A (ACTL6A)
• Synonyms: 53 kDa BRG1-associated factor A; Actin-related protein Baf53a; ArpNbeta; BRG1-associated factor 53A; BAF53A; INO80 complex subunit K
• Gene Name: ACTL6A
• Related Disease:
  Acquired aplastic anemia
  Advanced cancer
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Glioma
  Hepatocellular carcinoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  ACTL6A-related BAFopathy
  Cervical carcinoma
  Head-neck squamous cell carcinoma
  Rhabdomyosarcoma
  Squamous cell carcinoma
  Syndromic intellectual disability
  Bone osteosarcoma
  Colon adenoma
  Colon cancer
  Colon carcinoma
  Intellectual disability
  Osteosarcoma
• UniProt ID: ACL6A_HUMAN
• PDB ID: 6LTJ; 7VDV; 7Y8R
• Pfam ID: PF00022
• Sequence:
  MSGGVYGGDEVGALVFDIGSYTVRAGYAGEDCPKVDFPTAIGMVVERDDGSTLMEIDGDK
  GKQGGPTYYIDTNALRVPRENMEAISPLKNGMVEDWDSFQAILDHTYKMHVKSEASLHPV
  LMSEAPWNTRAKREKLTELMFEHYNIPAFFLCKTAVLTAFANGRSTGLILDSGATHTTAI
  PVHDGYVLQQGIVKSPLAGDFITMQCRELFQEMNIELVPPYMIASKEAVREGSPANWKRK
  EKLPQVTRSWHNYMCNCVIQDFQASVLQVSDSTYDEQVAAQMPTVHYEFPNGYNCDFGAE
  RLKIPEGLFDPSNVKGLSGNTMLGVSHVVTTSVGMCDIDIRPGLYGSVIVAGGNTLIQSF
  TDRLNRELSQKTPPSMRLKLIANNTTVERRFSSWIGGSILASLGTFQQMWISKQEYEEGG
  KQCVERKCP
• 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. Required for maximal ATPase activity of SMARCA4/BRG1/BAF190A and for association of the SMARCA4/BRG1/BAF190A containing remodeling complex BAF with chromatin/nuclear matrix. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and is required for the proliferation of neural progenitors. 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. Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Putative core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Thermogenesis (hsa04714)
  Hepatocellular carcinoma (hsa05225)
• Reactome Pathway:
  RMTs methylate histone arginines (R-HSA-3214858)
  UCH proteinases (R-HSA-5689603)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acquired aplastic anemia	DISCMKMX	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[7]
Prostate cancer	DISF190Y	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
ACTL6A-related BAFopathy	DISSOP0C	Moderate	Autosomal dominant	[9]
Cervical carcinoma	DIST4S00	moderate	Altered Expression	[10]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[11]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[12]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[11]
Syndromic intellectual disability	DISH7SDF	Moderate	Autosomal dominant	[13]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[6]
Colon adenoma	DISPMZ3U	Limited	Altered Expression	[5]
Colon cancer	DISVC52G	Limited	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[5]
Intellectual disability	DISMBNXP	Limited	Autosomal dominant	[13]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Actin-like protein 6A (ACTL6A).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Actin-like protein 6A (ACTL6A).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Actin-like protein 6A (ACTL6A).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Actin-like protein 6A (ACTL6A).	[20]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Actin-like protein 6A (ACTL6A).	[21]

3 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 Actin-like protein 6A (ACTL6A).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Actin-like protein 6A (ACTL6A).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Actin-like protein 6A (ACTL6A).	[19]

References

• [1] 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.
• [2] ACTL6A regulates follicle-stimulating hormone-driven glycolysis in ovarian cancer cells via PGK1.Cell Death Dis. 2019 Oct 24;10(11):811. doi: 10.1038/s41419-019-2050-y.
• [3] SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma.Cancer Med. 2019 Nov;8(16):7055-7064. doi: 10.1002/cam4.2569. Epub 2019 Sep 27.
• [4] Actin like-6A promotes glioma progression through stabilization of transcriptional regulators YAP/TAZ.Cell Death Dis. 2018 May 1;9(5):517. doi: 10.1038/s41419-018-0548-3.
• [5] ACTL6A expression promotes invasion, metastasis and epithelial mesenchymal transition of colon cancer.BMC Cancer. 2018 Oct 22;18(1):1020. doi: 10.1186/s12885-018-4931-3.
• [6] Actin-like protein 6A is a novel prognostic indicator promoting invasion and metastasis in osteosarcoma.Oncol Rep. 2017 Apr;37(4):2405-2417. doi: 10.3892/or.2017.5473. Epub 2017 Feb 23.
• [7] ACTL6A interacts with p53 in acute promyelocytic leukemia cell lines to affect differentiation via the Sox2/Notch1 signaling pathway.Cell Signal. 2019 Jan;53:390-399. doi: 10.1016/j.cellsig.2018.11.009. Epub 2018 Nov 15.
• [8] BAF53A regulates androgen receptor-mediated gene expression and proliferation in LNCaP cells.Biochem Biophys Res Commun. 2018 Oct 28;505(2):618-623. doi: 10.1016/j.bbrc.2018.09.149. Epub 2018 Sep 29.
• [9] 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.
• [10] Suppression of HPV E6 and E7 expression by BAF53 depletion in cervical cancer cells.Biochem Biophys Res Commun. 2011 Aug 26;412(2):328-33. doi: 10.1016/j.bbrc.2011.07.098. Epub 2011 Jul 29.
• [11] ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis.Cancer Cell. 2017 Jan 9;31(1):35-49. doi: 10.1016/j.ccell.2016.12.001. Epub 2016 Dec 29.
• [12] Failure to downregulate the BAF53a subunit of the SWI/SNF chromatin remodeling complex contributes to the differentiation block in rhabdomyosarcoma.Oncogene. 2014 May 1;33(18):2354-62. doi: 10.1038/onc.2013.188. Epub 2013 Jun 3.
• [13] Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. Hum Mutat. 2017 Oct;38(10):1365-1371. doi: 10.1002/humu.23282. Epub 2017 Jul 10.
• [14] 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.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] 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.
• [20] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [21] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.