Molecule Information

General Information of the Molecule (ID: Mol00234)

• Name: AT-rich interactive domain-containing protein 1A (ARID1A) ,Homo sapiens
• Synonyms: ARID domain-containing protein 1A; B120; BRG1-associated factor 250; BAF250; BRG1-associated factor 250a; BAF250A; Osa homolog 1; hOSA1; SWI-like protein; SWI/SNF complex protein p270; SWI/SNF-related; matrix-associated; actin-dependent regulator of chromatin subfamily F member 1; hELD; BAF250; BAF250A; C1orf4; OSA1; SMARCF1
• Molecule Type: Protein
• Gene Name: ARID1A
• Gene ID: 8289
• Location: chr1:26693236-26782104[+]
• Sequence:
  MAAQVAPAAASSLGNPPPPPPSELKKAEQQQREEAGGEAAAAAAAERGEMKAAAGQESEG
  PAVGPPQPLGKELQDGAESNGGGGGGGAGSGGGPGAEPDLKNSNGNAGPRPALNNNLTEP
  PGGGGGGSSDGVGAPPHSAAAALPPPAYGFGQPYGRSPSAVAAAAAAVFHQQHGGQQSPG
  LAALQSGGGGGLEPYAGPQQNSHDHGFPNHQYNSYYPNRSAYPPPAPAYALSSPRGGTPG
  SGAAAAAGSKPPPSSSASASSSSSSFAQQRFGAMGGGGPSAAGGGTPQPTATPTLNQLLT
  SPSSARGYQGYPGGDYSGGPQDGGAGKGPADMASQCWGAAAAAAAAAAASGGAQQRSHHA
  PMSPGSSGGGGQPLARTPQPSSPMDQMGKMRPQPYGGTNPYSQQQGPPSGPQQGHGYPGQ
  PYGSQTPQRYPMTMQGRAQSAMGGLSYTQQIPPYGQQGPSGYGQQGQTPYYNQQSPHPQQ
  QQPPYSQQPPSQTPHAQPSYQQQPQSQPPQLQSSQPPYSQQPSQPPHQQSPAPYPSQQST
  TQQHPQSQPPYSQPQAQSPYQQQQPQQPAPSTLSQQAAYPQPQSQQSQQTAYSQQRFPPP
  QELSQDSFGSQASSAPSMTSSKGGQEDMNLSLQSRPSSLPDLSGSIDDLPMGTEGALSPG
  VSTSGISSSQGEQSNPAQSPFSPHTSPHLPGIRGPSPSPVGSPASVAQSRSGPLSPAAVP
  GNQMPPRPPSGQSDSIMHPSMNQSSIAQDRGYMQRNPQMPQYSSPQPGSALSPRQPSGGQ
  IHTGMGSYQQNSMGSYGPQGGQYGPQGGYPRQPNYNALPNANYPSAGMAGGINPMGAGGQ
  MHGQPGIPPYGTLPPGRMSHASMGNRPYGPNMANMPPQVGSGMCPPPGGMNRKTQETAVA
  MHVAANSIQNRPPGYPNMNQGGMMGTGPPYGQGINSMAGMINPQGPPYSMGGTMANNSAG
  MAASPEMMGLGDVKLTPATKMNNKADGTPKTESKSKKSSSSTTTNEKITKLYELGGEPER
  KMWVDRYLAFTEEKAMGMTNLPAVGRKPLDLYRLYVSVKEIGGLTQVNKNKKWRELATNL
  NVGTSSSAASSLKKQYIQCLYAFECKIERGEDPPPDIFAAADSKKSQPKIQPPSPAGSGS
  MQGPQTPQSTSSSMAEGGDLKPPTPASTPHSQIPPLPGMSRSNSVGIQDAFNDGSDSTFQ
  KRNSMTPNPGYQPSMNTSDMMGRMSYEPNKDPYGSMRKAPGSDPFMSSGQGPNGGMGDPY
  SRAAGPGLGNVAMGPRQHYPYGGPYDRVRTEPGIGPEGNMSTGAPQPNLMPSNPDSGMYS
  PSRYPPQQQQQQQQRHDSYGNQFSTQGTPSGSPFPSQQTTMYQQQQQNYKRPMDGTYGPP
  AKRHEGEMYSVPYSTGQGQPQQQQLPPAQPQPASQQQAAQPSPQQDVYNQYGNAYPATAT
  AATERRPAGGPQNQFPFQFGRDRVSAPPGTNAQQNMPPQMMGGPIQASAEVAQQGTMWQG
  RNDMTYNYANRQSTGSAPQGPAYHGVNRTDEMLHTDQRANHEGSWPSHGTRQPPYGPSAP
  VPPMTRPPPSNYQPPPSMQNHIPQVSSPAPLPRPMENRTSPSKSPFLHSGMKMQKAGPPV
  PASHIAPAPVQPPMIRRDITFPPGSVEATQPVLKQRRRLTMKDIGTPEAWRVMMSLKSGL
  LAESTWALDTINILLYDDNSIMTFNLSQLPGLLELLVEYFRRCLIEIFGILKEYEVGDPG
  QRTLLDPGRFSKVSSPAPMEGGEEEEELLGPKLEEEEEEEVVENDEEIAFSGKDKPASEN
  SEEKLISKFDKLPVKIVQKNDPFVVDCSDKLGRVQEFDSGLLHWRIGGGDTTEHIQTHFE
  SKTELLPSRPHAPCPPAPRKHVTTAEGTPGTTDQEGPPPDGPPEKRITATMDDMLSTRSS
  TLTEDGAKSSEAIKESSKFPFGISPAQSHRNIKILEDEPHSKDETPLCTLLDWQDSLAKR
  CVCVSNTIRSLSFVPGNDFEMSKHPGLLLILGKLILLHHKHPERKQAPLTYEKEEEQDQG
  VSCNKVEWWWDCLEMLRENTLVTLANISGQLDLSPYPESICLPVLDGLLHWAVCPSAEAQ
  DPFSTLGPNAVLSPQRLVLETLSKLSIQDNNVDLILATPPFSRLEKLYSTMVRFLSDRKN
  PVCREMAVVLLANLAQGDSLAARAIAVQKGSIGNLLGFLEDSLAATQFQQSQASLLHMQN
  PPFEPTSVDMMRRAARALLALAKVDENHSEFTLYESRLLDISVSPLMNSLVSQVICDVLF
  LIGQS
• 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. Binds DNA non-specifically. 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 (By similarity).
• Uniprot ID: ARI1A_HUMAN
• Ensembl ID: ENSG00000117713
• HGNC ID: HGNC:11110

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Rucaparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [1]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Nonsense; p.Q456* (c.1366C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HMEC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: ARID1A-knockout (Q456*/Q456*) cells; N.A.; .; N.A.
• In Vivo Model: Male athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; ChIP assay
• Experiment for Drug Resistance: Tumor volume measurement assay

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Clear cell renal cell carcinoma [2]

• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Chemoresistance; Activation; hsa05207
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis; Immunohistochemical staining assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR144-3p promotes cell proliferation, metastasis, sunitinib resistance in clear cell renal cell carcinoma by downregulating ARID1A. and the downregulation of ARIDIA could promote the function of mir144-3p in cell proliferation, metastasis and chemoresistance.

Talazoparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [1]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Talazoparib
• Molecule Alteration: Nonsense; p.Q456* (c.1366C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HMEC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: ARID1A-knockout (Q456*/Q456*) cells; N.A.; .; N.A.
• In Vivo Model: Male athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; ChIP assay
• Experiment for Drug Resistance: Tumor volume measurement assay

Clinical Trial Drug(s) 2 drug(s) in total

Berzosertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [3]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Berzosertib
• Molecule Alteration: Nonsense; p.Q456* (c.1366C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: SMOV2 cells; Ovary; Homo sapiens (Human); CVCL_S920
• In Vitro Model: RMG-1 cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVSAYO cells; Ovary; Homo sapiens (Human); CVCL_3115
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVISE cells; Pelvi; Homo sapiens (Human); CVCL_3116
• In Vitro Model: OVAS cells; Ascites; Homo sapiens (Human); CVCL_0V12
• In Vitro Model: KOC7C cells; Pleural effusion; Homo sapiens (Human); CVCL_5307
• In Vitro Model: KK cells; Ascites; Homo sapiens (Human); CVCL_F844
• In Vitro Model: HCH1 cells; Ovary; Homo sapiens (Human); CVCL_DF05
• In Vivo Model: CD-1 Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ApoTox-Glo Triplex assay
• Mechanism Description: Defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis.

JQ1

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [4]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: JQ1
• Molecule Alteration: Nonsense; p.Q1148* (c.3442C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: OVCA429 cells; Ovary; Homo sapiens (Human); CVCL_3936
• In Vitro Model: TUOC1 cells; Ovary; Homo sapiens (Human); CVCL_L700
• In Vitro Model: SMOV2 cells; Ovary; Homo sapiens (Human); CVCL_S920
• In Vitro Model: RMGII cells; Ascites; Homo sapiens (Human); CVCL_2803
• In Vitro Model: RMGI cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVAS cells; Ascites; Homo sapiens (Human); CVCL_0V12
• In Vitro Model: OV207 cells; Ovary; Homo sapiens (Human); CVCL_A404
• In Vitro Model: KOC7C cells; Pleural effusion; Homo sapiens (Human); CVCL_5307
• In Vitro Model: HAC2 cells; Ascites; Homo sapiens (Human); CVCL_8354
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The inhibitory effects on residual SWI/SNF function, specifically via reduced ARID1B expression, may explain the enhanced sensitivity of ARID1A mutant cells to BET inhibitors.

Investigative Drug(s) 1 drug(s) in total

VE-821

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [3]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: VE-821
• Molecule Alteration: Nonsense; p.Q456* (c.1366C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: SMOV2 cells; Ovary; Homo sapiens (Human); CVCL_S920
• In Vitro Model: RMG-1 cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVSAYO cells; Ovary; Homo sapiens (Human); CVCL_3115
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVISE cells; Pelvi; Homo sapiens (Human); CVCL_3116
• In Vitro Model: OVAS cells; Ascites; Homo sapiens (Human); CVCL_0V12
• In Vitro Model: KOC7C cells; Pleural effusion; Homo sapiens (Human); CVCL_5307
• In Vitro Model: KK cells; Ascites; Homo sapiens (Human); CVCL_F844
• In Vitro Model: HCH1 cells; Ovary; Homo sapiens (Human); CVCL_DF05
• In Vivo Model: CD-1 Nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ApoTox-Glo triplex assay
• Mechanism Description: Defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.93E-01; Fold-change: -5.38E-03; Z-score: -1.32E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.08E-08; Fold-change: 2.06E+00; Z-score: 3.59E+00

Kidney cancer [ICD-11: 2C90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Kidney
• The Specified Disease: Kidney cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.33E-04; Fold-change: -7.77E-01; Z-score: -1.18E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.70E-01; Fold-change: -1.93E-01; Z-score: -3.67E-01

References

• Ref 1: ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP InhibitorsCancer Discov. 2015 Jul;5(7):752-67. doi: 10.1158/2159-8290.CD-14-0849. Epub 2015 Jun 11.
• Ref 2: Mir-144-3p Promotes Cell Proliferation, Metastasis, Sunitinib Resistance in Clear Cell Renal Cell Carcinoma by Downregulating ARID1A. Cell Physiol Biochem. 2017;43(6):2420-2433. doi: 10.1159/000484395. Epub 2017 Oct 27.
• Ref 3: ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1ANat Commun. 2016 Dec 13;7:13837. doi: 10.1038/ncomms13837.
• Ref 4: ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitorsOncogene. 2018 Aug;37(33):4611-4625. doi: 10.1038/s41388-018-0300-6. Epub 2018 May 15.