ABSTRACT
We have recently discovered that AT-rich interactive domain-containing protein 1A (ARID1A) protects telomere cohesion through regulation of the cohesin subunit stromal antigen 1 (STAG1). ARID1A inactivation results in mitotic defects and negatively selects gross chromosomal aberrations, resulting in preservation of genomic stability in ARID1A-mutated cancers. These findings explain the long-standing paradox between mitotic defects caused by ARID1A inactivation and the lack of genomic instability in ARID1A-mutated cancers.
KEYWORDS: ARID1A, SWI/SNF, STAG1, OCCC, telomere, mitotic defects, genomic instability
AT-rich interactive domain-containing protein 1A (ARID1A) encodes a subunit of the multi-subunit Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex. The SWI/SNF complex remodels chromatin in an ATP-dependent manner and regulates a number of chromatin-related processes, including DNA replication, repair, and transcription.1 ARID1A is frequently mutated in a range of human cancers and has the highest mutation rate of the SWI/SNF subunits. ARID1A functions as a tumor suppressor where mutations, the majority of which are nonsense or frame-shift, result in a loss of protein expression. Notably, ARID1A is mutated in up to 60% of ovarian clear cell carcinoma (OCCC) cases.2 OCCC is the most lethal histological subtype of ovarian cancer when diagnosed at advanced stages and refractory to chemotherapy, including the anti-mitotic compound paclitaxel (PTX).3
In addition to regulating chromatin accessibility at promoters and enhancers,4 ARID1A also has an important function in maintaining genomic integrity. For example, ARID1A interacts with topoisomerase IIa (TOP2A), which allows decatenation of newly replicated sister chromatids. Consequently, ARID1A inactivation results in mitotic defects, such as anaphase bridge formation, leading to chromosomal instability and polyploidy.5 Paradoxically, ARID1A-mutated cancers are not marked by widespread genomic and chromosomal instability. For instance, OCCC exhibits significantly lower chromosomal instability as compared to high-grade serous ovarian carcinoma based on DNA copy number alterations.6 Additionally, our study revealed through data mining of The Cancer Genome Atlas that ARID1A-mutant cancers, including uterine corpus endometrial carcinoma, stomach adenocarcinoma, and colon adenocarcinoma, exhibit significantly less genome instability based on copy number variations.7 Our study reconciles this paradox and reveals a molecular mechanism by which ARID1A-inactivated cancers maintain genomic stability (Figure 1).7
Figure 1.
AT-rich interactive domain-containing protein 1A (ARID1A) inactivation selects against gross chromosomal aberrations and enriches for cancer cells with preserved genomic stability. ARID1A wildtype cells maintain telomere cohesion through stromal antigen 1 (STAG1) expression and undergo normal mitosis. However, ARID1A-inactivated cells exhibit defects in telomere cohesion through reduced STAG1 expression. Consequently, ARID1A-inactivated cells develop gross chromosomal aberrations and mitotic defects that lead to cell death. While this cell population is negatively selected, a separate surviving cell population is enriched that exhibits preserved genomic stability and decreased sensitivity to paclitaxel (PTX).
We identified that a key player in mediating genomic stability of ARID1A-inactivated cells is stromal antigen 1 (STAG1), which is a subunit of the cohesin complex. In addition to STAG1, the cohesin complex consists of structural maintenance of chromosomes 1 (SMC1), structural maintenance of chromosomes 3 (SMC3), RAD21 cohesion complex component (SCC1), and stromal antigen 2 (STAG2) subunits. STAG1 is mutually exclusive with STAG2, where both mediate sister chromatid cohesion but at different locations. For instance, chromatin cohesion at telomeres is mediated by STAG1, while at centromeres is mediated by STAG2.8 Indeed, STAG1 is essential for faithful chromosome segregation during mitosis and its inactivation results in chromosomal mis-segregation during mitosis.9 Moreover, STAG1 is mutated in a range of cancers and considered a tumor suppressor because its loss promotes genomic instability.10
Our study shows that loss of STAG1 plays a key role in the selection against ARID1A-inactivated cells exhibiting gross genomic instability. We found ARID1A binds the promoter of STAG1 to activate its expression. Consequently, ARID1A inactivation results in loss of STAG1 expression and is associated with defective telomere cohesion and telomere damage. Consistently, ARID1A inactivation results in chromosomal defects during mitosis and promotes genomic instability. This was evident based on the formation of anaphase bridges and lagging chromosomes. However, the ARID1A inactivated cells with severe mitotic defects were selectively eliminated during mitosis. Consequently, ARID1A inactivation favors the propagation of cells with genomic stability. Indeed, ARID1A inactivation significantly reduced colony formation capability of single cells from the G2/M phase, but not G1 phase, of the cell cycle. This phenotype is recapitulated when STAG1 is knocked down in ARID1A-wildtype cells. Additionally, restoration of STAG1 is sufficient to rescue defective telomere cohesion and the mitotic defects in ARID1A-inactivated cells. Because of the development of gross chromosomal aberrations, ARID1A-inactivated cells undergoing mitosis are negatively selected through the induction of apoptosis. However, the outcome is the enrichment of ARID1A-inactivated cells lacking genomic instability and reduced sensitivity to mitosis-targeting compounds, such as PTX (Figure 1). The results of this study indicate that ARID1A serves a tumor suppressive role by promoting STAG1 expression to protect telomere cohesion and maintain mitotic integrity. This newly discovered regulation uncovers a novel role of ARID1A in preserving genomic stability.
Funding Statement
This work was supported by National Cancer Institute [NIH/NCI R01CA202919].
Abbreviations
- OCCC
ovarian clear cell carcinoma
- ARID1A
AT-rich interactive domain-containing protein 1A
- SWI/SNF
Switch/Sucrose Non-Fermentable
- PTX
paclitaxel
- TOP2A
topoisomerase IIa
- STAG1
stromal antigen 1
- STAG2
stromal antigen 2
Disclosure of Conflict of Interest
No potential conflicts of interest were disclosed.
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