ARID1A-mutated ovarian cancers depend on HDAC6 activity

Bitler, Benjamin G.; Wu, Shuai; Park, Pyoung Hwa; Yan, Hai; Aird, Katherine M.; Wang, Yemin; Zhai, Yali; Kossenkov, Andrew V.; Vara-Ailor, Ana; Rauscher, Frank J.; Zou, Weiping; Speicher, David W.; Huntsman, David G.; Conejo-Garcia, José R.; Cho, Kathleen R.; Christianson, D.W.; Zhang, Rugang

doi:10.1038/ncb3582

Cited by 180 publications

(182 citation statements)

References 41 publications

(82 reference statements)

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“…60 Therefore, the lack in activity we observed in SK-OV-3-Luc ovarian cancer cells, might at least be partially explained by the fact that these cells are ARID1A mutated but do not express p53. 60 Therefore, the lack in activity we observed in SK-OV-3-Luc ovarian cancer cells, might at least be partially explained by the fact that these cells are ARID1A mutated but do not express p53.…”

Section: Discussionmentioning

confidence: 83%

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

Depetter

Geurs

Vreese

et al. 2019

Intl Journal of Cancer

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Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 inhibitors (Tubathian A, Tubastatin A, Tubacin and Ricolinostat) and a non‐selective HDAC inhibitor (Vorinostat) were evaluated on cancer cell lines derived from multiple tumour types in both an in vitro and in vivo setting as potential cancer therapeutics. Selective HDAC6 inhibitors resulted in α‐tubulin acetylation with no impact on histone acetylation but failed to show any anti‐cancer properties. Only the use of high concentrations of selective HDAC6 inhibitors resulted in co‐inhibition of other HDAC enzymes and consequently in reduced growth, migratory and/or invasive activity of cancer cells in vitro as well as in vivo. The specificity of HDAC6 inhibition was confirmed using a CRISPR/Cas9 knockout cell line. Our results suggest that selective HDAC6 inhibitors may fall short as potential single agent anti‐cancer drugs and prove that many previous data regarding this promising class of compounds need to be interpreted with great care due to their use in high concentrations resulting in low selectivity and potential off‐target effects.

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Section: Discussionmentioning

confidence: 83%

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

Depetter

Geurs

Vreese

et al. 2019

Intl Journal of Cancer

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“…Importantly, ARID1A is the most frequently mutated chromatin regulator across all human cancers (Kadoch et al, 2013). In particular, Ovarian Clear Cell Carcinoma (OCCC) carries the highest prevalence of ARID1A mutations [~57%] (Bitler et al, 2015; Bitler et al, 2017; Jones et al, 2010). Conversely, ARID1B is rarely found mutated.…”

Section: Introductionmentioning

confidence: 99%

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

et al. 2018

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Summary AT-rich interactive domain-containing protein 1A and 1B (ARID1A, ARID1B) are mutually exclusive subunits of the chromatin remodeler SWI/SNF. ARID1A is the most frequently mutated chromatin regulator across all cancers, and ovarian clear cell carcinoma (OCCC) carries the highest prevalence of ARID1A mutations (~57%). Despite evidence implicating ARID1A in tumorigenesis, the mechanism remains elusive. Here, we demonstrate that in OCCC ARID1A binds active regulatory elements. Depletion of ARID1A represses RNA Polymerase II (RNAPII) transcription, but results in modest changes to accessibility. Specifically, pausing of RNAPII is severely impaired after loss of ARID1A. Compromised pausing results in transcriptional dysregulation of active genes, which is compensated by upregulation of ARID1B. However, a subset of ARID1A-dependent genes is not rescued by ARID1B, including many p53 and estrogen receptor (ESR1) targets. Our results provide new insight on ARID1A-mediated tumorigenesis and unveil new functions of SWI/SNF in modulating RNAPII dynamics.

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“…This was mediated via upregulation of PIK3IP1, a direct target of EZH2, and selectivity was further enhanced upon inhibition of PI3K-AKT signalling [21]. Subsequent work by Bitler et al has shown that ARID1A-mutated ovarian cancers are selectively dependent on HDAC6 activity, due to HDAC6 upregulation in ARID1A mutant cells that mechanistically inactivates the apoptosis-promoting function of TP53 due to deacetylation of histone lysine 120 [22]. The work showed that treating ARID1A-mutated tumours with the small molecule HDAC6 inhibitor, ACY1215, showed a survival benefit in vivo.…”

mentioning

confidence: 99%

Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers

Khalique

Naidoo

Attygalle

et al. 2018

The Journal of Pathology CR

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ARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ARID1A defects. However, the accuracy of ARID1A immunohistochemistry (IHC) as a surrogate for mutation status has not fully been established for patient stratification in clinical trials. Here we tested whether ARID1A IHC could reliably predict ARID1A mutations identified by next‐generation sequencing. Three commercially available antibodies – EPR13501 (Abcam), D2A8U (Cell Signaling), and HPA005456 (Sigma) – were optimised for IHC using cell line models and human tissue, and screened across a cohort of 45 gynaecological tumours. IHC was scored independently by three pathologists using an immunoreactive score. ARID1A mutation status was assessed using two independent sequencing platforms and the concordance between ARID1A mutation and protein expression was evaluated using Receiver Operating Characteristic statistics. Overall, 21 ARID1A mutations were identified in 14/43 assessable tumours (33%), the majority of which were predicted to be deleterious. Mutations were identified in 6/17 (35%) ovarian clear cell carcinomas, 5/8 (63%) ovarian endometrioid carcinomas, 2/5 (40%) endometrial carcinomas, and 1/7 (14%) carcinosarcomas. ROC analysis identified greater than 95% concordance between mutation status and IHC using a modified immunoreactive score for all three antibodies allowing a definitive cut‐point for ARID1A mutant status to be calculated. Comprehensive assessment of concordance of ARID1A IHC and mutation status identified EPR13501 as an optimal antibody, with 100% concordance between ARID1A mutation status and protein expression, across different gynaecological histological subtypes. It delivered the best inter‐rater agreement between all pathologists, as well as a clear cost‐benefit advantage. This could allow patients to be accurately stratified based on their ARID1A IHC status into early phase clinical trials.

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ARID1A-mutated ovarian cancers depend on HDAC6 activity

Cited by 180 publications

References 41 publications

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

Optimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers

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