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

Changjie Wu,Joong Sup Shim,Baoyuan Zhang,Junfang Lyu,Eun Ju Yang,Yifan Liu

doi:10.1038/s41467-018-05694-4

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.

Highlights

AT-rich interactive domain 1A (ARID1A), a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor with a high frequency of inactivating mutations in many cancers
In vitro growth rates for the ARID1A+/+ and ARID1A−/− HCT116 colorectal cancer (CRC) cells were similar in short-term culture (Supplementary Fig. 2a), which was in agreement with previous reports[16,19,34]
histone deacetylase 6 (HDAC6) has recently been identified as a target gene of ARID1A for transcription repression in ovarian clear cell carcinoma (OCCC); OCCC cells with ARID1A loss were shown to be sensitized to HDAC6 inhibition[19]

Summary

Introduction

ARID1A, a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor with a high frequency of inactivating mutations in many cancers. 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. Synthetic lethality is a genetic interaction between two or more genes where a single gene deficiency does not affect cell viability, but the combination of both gene deficiencies causes lethality This concept has been widely exploited in cancer therapy because many types of cancer have loss-of-function mutations in tumor-suppressor genes that are not readily targetable. Inhibiting the synthetic lethality targets resulted in selective vulnerabilities in ARID1A mutant OCCC, CRC, and breast cancer cells[16,17,18,19] These studies suggested that ARID1A, as an epigenetic machinery component, may have various genetic and functional interdependencies with other epigenetic components to affect cell survival. We further explore a mechanism whereby the ARID1A and AURKA pathways converge on CDC25C to induce G2/M arrest and apoptosis in CRC cells

Methods

Results

Conclusion