Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells

Changjie Wu, Junfang Lyu, Eun Ju Yang, Yifan Liu, Baoyuan Zhang and Joong Sup Shim ()
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Changjie Wu: University of Macau, Avenida da Universidade
Junfang Lyu: University of Macau, Avenida da Universidade
Eun Ju Yang: University of Macau, Avenida da Universidade
Yifan Liu: University of Macau, Avenida da Universidade
Baoyuan Zhang: University of Macau, Avenida da Universidade
Joong Sup Shim: University of Macau, Avenida da Universidade

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract ARID1A, a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor with a high frequency of inactivating mutations in many cancers. Therefore, ARID1A deficiency has been exploited therapeutically for treating cancer. Here we show that ARID1A has a synthetic lethal interaction with aurora kinase A (AURKA) in colorectal cancer (CRC) cells. Pharmacological and genetic perturbations of AURKA selectively inhibit the growth of ARID1A-deficient CRC cells. Mechanistically, ARID1A occupies the AURKA gene promoter and negatively regulates its transcription. Cells lacking ARID1A show enhanced AURKA transcription, which leads to the persistent activation of CDC25C, a key protein for G2/M transition and mitotic entry. Inhibiting AURKA activity in ARID1A-deficient cells significantly increases G2/M arrest and induces cellular multinucleation and apoptosis. This study shows a novel synthetic lethality interaction between ARID1A and AURKA and indicates that pharmacologically inhibiting the AURKA–CDC25C axis represents a novel strategy for treating CRC with ARID1A loss-of-function mutations.

Date: 2018
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DOI: 10.1038/s41467-018-05694-4

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