Table 3.
Effects of ARID1A loss of function mutations and opportunities for cancer therapy.
| Affected Cell Processes | Result | Actionable Therapy Approach | References |
|---|---|---|---|
| Gene expression changes: | |||
| p300/CRB histone acetyltransferase interaction | Due to lost p300/CRB interactions with ARID1A, changes in H3K27ac marks lead to many gene expression changes | [63] | |
| RNAPII pausing | Loss of normal RNAPII pausing may be due to reduced promoter acetylation and results in decreased gene expression | [64] | |
| HDAC6 deacetylase activation, p53 deacetylation | HDAC6 is activated by ARID1A reduction. In turn, p53 K120 is deacetylated (which inhibits apoptosis) | HDAC6 inhibitor | [65] |
| ARID1B | As an ARID1A homolog, ARID1B is left to restore most of the functions | BRD2 (BET, required for ARID1B transcription) inhibitors | [66] |
| YES1 deregulation | In ARID1A deficient cell line model treated with dasatinib, YES1 was identified as the main target gene | YES1 inhibitor (dasatinib) | [67] |
| Telomere/cell division: | |||
| STAG1 (cohesin protein) reduction | Reduced STAG1 leads to decreased mitotic telomere cohesion | [68] | |
| TOP2A (topoisomerase) interaction loss | TOP2A interactions with SWI/SNF complex ATPase BRG1 are lost/reduced. This causes replication stress through reduced sister chromatid decatenation and anaphase bridge formation during mitosis | [69,70] | |
| TERT (telomerase reverse transriptase) upregulation | TERT promoter is upregulated in ARID1A deficient cells (increased survival) | ATR inhibitor | [71] |
| DNA damage reparation: | |||
| HR (homologous DSB repair) | ARID1A interacts and activates ATR and is required for DNA end processing (RPA and RAD51 loading), as well as G2-M cell-cycle arrest maintenance | PARP inhibitor | [72] |
| NHEJ (non-homologous end joining) | ARID1A/B are required for KU70/KU80 protein recruitment to DSB | cisplatin | [73] |
| MMR (miss match repair) | ARID1A may interact and direct MSH2 to MMR sites | PD-L1 inhibitor | [61] |
| NER (nucleotide excision repair) | ARID1A/B required for XPA (NER protein) requirement | [74] | |
| ROS (reactive oxygen species) formation | Reduces SLC7A11 levels to impair antioxidant GSH production | ROS inducers (e.g., HSP90 inhibitor, elesclomol) | [75,76] |
| PI3K/AKT/mTOR pathway: | |||
| PI3K/AKT/mTOR regulation | Mutually inclusive KRAS, PIK3CA, and PTEN mutations | [77] | |
| ANXA1 (AKT activator) upregulation | Upregulation by ARID1A loss | AKT inhibitor | [78] |
| PIK3IP1(PI3K inhibitor) downregulation | Downregulation by ARID1A loss (through EZH2 methyltransferase activation) | PI3K, EZH2, HDAC2 inhibitors | [79] |
| Protein interactions: | |||
| E3 ubiquitin ligase interaction | ARID1 forms E3 ubiquitin ligase, and mutations result in decreased ubiquitination of H2B histones | [80] | |
| MYC interaction | Interaction with and regulation of MYC | [81] | |