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

Author

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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)

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.

Suggested Citation

  • Changjie Wu & Junfang Lyu & Eun Ju Yang & Yifan Liu & Baoyuan Zhang & Joong Sup Shim, 2018. "Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05694-4
    DOI: 10.1038/s41467-018-05694-4
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