The emerging roles of ARID1A in tumor suppression

Abstract

ARID1A has emerged as a tumor suppressor gene, which is mutated in a broad spectrum of cancers, especially in those arising from ectopic or eutopic endometrium. As a subunit of SWI/SNF chromatin remodeler, ARID1A facilitates target-specific binding of SWI/SNF complexes to chromatin, thereby altering the accessibility of chromatin to a variety of nuclear factors. In human cancer, ARID1A possesses not only features of a gatekeeper, regulating cell cycle progression, but also features of a caretaker, preventing genomic instability. An increasing body of evidence suggests crosstalk between ARID1A and PI3K/Akt pathways, and between ARID1A and p53. In this review, we discuss the spectrum of ARID1A alterations in cancers, tumor suppression mechanisms of ARID1A, oncogenic pathways cooperating with ARID1A, and clinical implications of ARID1A mutation.

Keywords: ARID1A; PI3K; SWI/SNF; chromatin remodeling complex; clear cell carcinoma; endometrial cancer; endometrioid carcinoma; gastric cancer; ovarian cancer; tumor suppressor gene.

Figure 1. Mutation frequency of ARID1A among human cancers. A total of 594 mutated samples from 5160 tumors belonging to 25 different tumor types have been reported (as of January 2014). Among all neoplastic diseases analyzed, ARID1A mutation is most prevalent in ovarian clear cell carcinoma, uterine endometrioid carcinoma, and ovarian endometrioid carcinoma, all of which are derived from either ectopic or eutopic endometrial epithelium. ARID1A mutations are associated with loss of ARID1A expression as shown in an example of uterine endometrioid carcinoma while normal endometrium expresses ARID1A protein.

Figure 2. The relationship between ARID1A mutation and PIK3CA mutation (A), and between ARID1A mutation and TERT promoter mutation (B). Green boxes are tumors harboring somatic ARID1A mutations while red boxes are tumors with either PIK3CA mutation or TERT promoter mutation. Each box represents an individual tumor. The total number of tumors, the odds ratio (OR) and P values are shown above each diagram.