Fig. 6

AURKA–CDC25C axis is a target for synthetic lethality in ARID1A-KO colorectal cancer cells. a Immunoblots showing upregulation of AURKA and phosphorylated CDC25C at Ser198 levels and downregulation of phosphorylated CDC2 at Tyr15 level in ARID1A^−/− HCT116 cells. b, c Inhibition of CDC25C phosphorylation at Ser198 and increased phosphorylation of CDC2 at Tyr15 by AURKA silencing (b) and AURKAi treatment (c). d Immunofluorescence analysis of CDC25C localization in ARID1A isogenic cells treated with or without AURKA siRNA. Scale bars, 20 µm. e Synthetic lethality in ARID1A^−/− HCT116 cells by CDC25 inhibitor II. f Synthetic lethality in ARID1A^−/− HCT116 cells by PLK1 siRNA (siPLK1). Error bars represent s.d. *P < 0.05; **P < 0.01, Student’s t test. g Working model of the synthetic lethality between ARID1A and AURKA. In ARID1A wild-type (WT) cells, AURKA expression is negatively regulated by ARID1A, thereby reducing the activity of AURKA downstream pathway, including PLK1 and CDC25C. In ARID1A mutant (MT) cells, AURKA-PLK1-CDC25C pathway is upregulated. In addition, CDC25C activity is negatively regulated by ARID1A–ATR–CHK (checkpoint kinase) pathway under DNA damage conditions, thereby strictly controlling the CDC25 activity in ARID1A WT cells. In ARID1A MT cells, ARID1A–ATR–CHK pathways is impaired and thus CDC25C activity is de-repressed, causing it in hyper-active state. In this condition, cells can be addicted to AURKA–CDC25C pathway for cell survival and proliferation. Therefore, AURKA–CDC25C axis becomes a target for synthetic lethality in ARID1A-deficient cells