ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response

Nagarajan, Sankari; Rao, Shalini; Sutton, Joseph; Cheeseman, Danya; Dunn, Shanade; Papachristou, Evangelia K.; Prada, Jose-Enrique Gonzalez; Couturier, Dominique‐Laurent; Kumar, Sanjeev; Kishore, Kamal; Chilamakuri, Chandra Sekhar Reddy; Glont, Silvia-Elena; Goode, Emily Archer; Brodie, Cara; Guppy, Naomi; Natrajan, Rachael; Bruna, Alejandra; Caldas, Carlos; Russell, Alasdair; Siersbæk, Rasmus; Yusa, Kosuke; Chernukhin, Igor; Carroll, Jason S.

doi:10.1038/s41588-019-0541-5

Cited by 127 publications

(119 citation statements)

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“…In breast cancer, ARID1A binds and represses enhancers containing estrogen receptor-binding elements through co-recruitment of HDAC1, and ARID1A loss results in H4 acetylation, BRD4 recruitment, and subsequent transcription (Nagarajan et al, 2020). However, in that study, ARID1A knockout did not result in differential H3K27ac (Nagarajan et al, 2020). Our data suggest a distinct role for ARID1A-P300 antagonism in the regulation of SE chromatin accessibly and H3K27ac deposition in the endometrial epithelium.…”

Section: Discussionmentioning

confidence: 50%

“…In embryonic stem cells, mutations in SWI/SNF catalytic subunit Brahma result in enhancer reprogramming (Gao et al, 2019). In breast cancer, ARID1A binds and represses enhancers containing estrogen receptor-binding elements through co-recruitment of HDAC1, and ARID1A loss results in H4 acetylation, BRD4 recruitment, and subsequent transcription (Nagarajan et al, 2020). However, in that study, ARID1A knockout did not result in differential H3K27ac (Nagarajan et al, 2020).…”

Section: Discussionmentioning

confidence: 62%

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ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation

et al. 2020

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 62%

ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation

et al. 2020

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“…Interestingly, the combined loss of BAF250A/ARID1A and gain of expressed mutated PI3K subunit PIK3CA H1047R results in partial EMT in the endometrial epithelium (176). Resistance to ER antagonists in breast cancer was recently attributed to loss of ARID1A, which reduced HDAC1 activity and increased H4K acetylation-sensitizing the cancer cells to BRD4 inhibition (177). Nucleophosmin 1 (NPM1) is another well-studied histone chaperone [reviewed by (178)] with a role in EMT/invasion (179)(180)(181).…”

Section: Remodeling Our Understanding Of Chromatin Machinery In Emtmentioning

confidence: 99%

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

Lavin

Tiwari

2020

Front. Oncol.

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Epithelial to mesenchymal transition (EMT) is the process whereby a polarized epithelial cell ceases to maintain cell-cell contacts, loses expression of characteristic epithelial cell markers, and acquires mesenchymal cell markers and properties such as motility, contractile ability, and invasiveness. A complex process that occurs during development and many disease states, EMT involves a plethora of transcription factors (TFs) and signaling pathways. Whilst great advances have been made in both our understanding of the progressive cell-fate changes during EMT and the gene regulatory networks that drive this process, there are still gaps in our knowledge. Epigenetic modifications are dynamic, chromatin modifying enzymes are vast and varied, transcription factors are pleiotropic, and signaling pathways are multifaceted and rarely act alone. Therefore, it is of great importance that we decipher and understand each intricate step of the process and how these players at different levels crosstalk with each other to successfully orchestrate EMT. A delicate balance and fine-tuned cooperation of gene regulatory mechanisms is required for EMT to occur successfully, and until we resolve the unknowns in this network, we cannot hope to develop effective therapies against diseases that involve aberrant EMT such as cancer. In this review, we focus on data that challenge these unknown entities underlying EMT, starting with EMT stimuli followed by intracellular signaling through to epigenetic mechanisms and chromatin remodeling.

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“…Increased activities of other proteins were rather treatment-specific (e.g., p-JNK in TAM-resistant cells) or cell line-specific (e.g., p-P44/42 in T47D). Notably, ATF3 has been found to be among the top depleted genes in a CRISPR screen with MCF7 cells treated with TAM or Fulvestrant [ 21 ], thus confirming its role in endocrine therapy response ( Figure 2 a). We then tested if ATF3 was already induced at timepoints earlier than one month of treatment with endocrine therapies.…”

Section: Resultsmentioning

confidence: 70%

Time-Resolved Profiling Reveals ATF3 as a Novel Mediator of Endocrine Resistance in Breast Cancer

Borgoni

Sofyalı

Soleimani

et al. 2020

Cancers

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Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express Estrogen Receptor α account for around 70% of cases and are mostly treated with targeted endocrine therapy. However, depending on the degree of severity of the disease at diagnosis, 10 to 40% of these tumors eventually relapse due to resistance development. Even though recent novel approaches as the combination with CDK4/6 inhibitors increased the overall survival of relapsing patients, this remains relatively short and there is a urgent need to find alternative targetable pathways. In this study we profiled the early phases of the resistance development process to uncover drivers of this phenomenon. Time-resolved analysis revealed that ATF3, a member of the ATF/CREB family of transcription factors, acts as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. ATF3 was found to be essential in controlling crucial processes such as proliferation, cell cycle, and apoptosis during the early response to treatment through the regulation of MAPK/AKT signaling pathways. Its essential role was confirmed in vivo in a mouse model, and elevated expression of ATF3 was verified in patient datasets, adding clinical relevance to our findings. This study proposes ATF3 as a novel mediator of endocrine resistance development in breast cancer and elucidates its role in the regulation of downstream pathways activities.

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ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response

Cited by 127 publications

References 50 publications

ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation

ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

Time-Resolved Profiling Reveals ATF3 as a Novel Mediator of Endocrine Resistance in Breast Cancer

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