Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

Abstract

ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres. ARID1A3 encodes BAF250 (also known as p270), which interacts with the ATPase subunit, BRG1 or BRM, and a set of core subunits (BAF47, BAF155, and BAF170) to form the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. By utilizing the energy from ATP hydrolysis, these complexes rearrange the distribution of nucleosomes, thereby modifying chromatin configuration and DNA accessibility to cellular machineries involved in transcription, DNA replication, DNA methylation, and DNA repair (1-3).The discovery of molecular genetic aberrations in chromatin remodelers converged genetic and epigenetic dysregulation, which contributes to the development and progression of numerous diseases, including cancer. Somatic ARID1A mutations were first discovered in ovarian clear cell carcinoma (4, 5) and subsequently reported in endometrium-derived carcinomas and several other cancer types (6, 7). Mutations of ARID1A occur throughout the entire coding sequence, mostly frameshift and nonsense mutations, thereby resulting in a loss of ARID1A protein expression. Hence, ARID1A is implicated as a tumor suppressor, and indeed, functional studies have demonstrated that ARID1A loss can promote tumorigenesis by affecting proliferation, differentiation, and apoptosis (8 -10). At the molecular level, our previous study demonstrated that the ARID1A complex interacted and collaborated with p53 to regulate transcription of several effectors including CDKN1A encoding p21 (8). In genetically engineered mice, whereas Arid1a deletion by itself is insufficient to transform cells, codeletion of Arid1a with either Pten or Pik3ca is required to drive the formation of ovarian endometrioid and clear cell-like carcinomas, respectively (11, 12).To further elucidate molecular mechanisms of ARID1A in preventing tumorigenesis, we sought to identify additional molecular genetic alterations that tend to be absent in ARID1A mutated tumors. The nature of ...

ARID1A‐SIN3A drives retinoic acid‐induced neuroblastoma differentiation by transcriptional repression of TERT

“…Genomic profiling of NB has identified inactivation mutations of both ARID1A and ARID1B . ARID1A has previously been shown to reduce transcription of p53‐regulated genes, CDKN1A and histone deacetylase 6 ( HDAC6 ) as well as playing a cosuppressive role in ovarian cancer alongside the SIN3A complex . In accordance with previous studies, we show that ARID1A co‐occupies the TERT promoter with SIN3A to suppress TERT expression and, furthermore, that this effect occurs specifically during NB differentiation.…”

“…[13][14][15] Emerging data demonstrate that ARID1A interacts with the TERT promoter region to cause chromatin remodeling 16,17 and potentially recruit transcriptional regulators such as the glucocorticoid receptor (GR), 18 histone deacetylase 6 (HDAC6), 19 and SIN3 transcription regulator family member A (SIN3A). 20 In this study, we demonstrate an inverse association between ARID1A and TERT in cell lines and NB patient cohorts. In addition, we report that the SIN3A suppressor complex is recruited to the promoter via ARID1A to reduce TERT expression and allow NB cells to progress to a more differentiated, low-risk phenotype.…”

“…ARID1A recruits SIN3A as a corepressor of TERT in a number of cancers . We examined TERT promoter occupancy by ARID1A and SIN3A using ChIP‐qPCR during RA treatment of NB cells (Figure A).…”

“…3.2 | ARID1A-SIN3A co-occupancy on the TERT promoter is required for reduction of TERT expression during RA-induced NB differentiation ARID1A recruits SIN3A as a corepressor of TERT in a number of cancers. 20 We examined TERT promoter occupancy by ARID1A and SIN3A using ChIP-qPCR during RA treatment of NB cells (Figure 2A).…”

“…Inactivated SWI/SNF mutation or loss of the AT‐rich interaction domain 1A (ARID1A) subunit is frequently observed in various solid tumors including NB . Emerging data demonstrate that ARID1A interacts with the TERT promoter region to cause chromatin remodeling and potentially recruit transcriptional regulators such as the glucocorticoid receptor (GR), histone deacetylase 6 (HDAC6), and SIN3 transcription regulator family member A (SIN3A) …”