Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer

Ding, Yong; Ni, Li; Dong, Baijun; Guo, Wangxin; Wei, Hui; Chen, Qilong; Yuan, Huairui; Han, Ying; Chang, Han-Wen; Kan, Shan; Wang, Xuege; Pan, Qiang; Wu, Po-Liang; Peng, Chao; Qiu, Tong; Li, Qintong; Xue, Wei; Qin, Jun

doi:10.1172/jci123557

Cited by 60 publications

(72 citation statements)

References 66 publications

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“…Most recently, two studies demonstrated that SMARCA4 was required for growth of prostatic adenocarcinoma cells 69,75 , as also confirmed by our results (Fig. 2).…”

Section: Discussionsupporting

confidence: 91%

“…2). Localized PCa has previously been reported to show higher SMARCA4 and lower SMARCA2 expression than benign prostate tissue 69,[75][76][77] . We further report an overexpression of SMARCA4 in CRPC and especially in CRPC-NE, in contrast to lower expression in early PCa.…”

Section: Discussionmentioning

confidence: 99%

“…and SMARCA4 in PCa, identified through a CRISPR-Cas9 screen 75 . This could have highly relevant translational implications, as 30% of clinically localized PCa cases and as many as 80% of CRPC demonstrate homozygous PTEN deletion 5,9 .…”

Section: Recent Work By Ding Et Al Specifically Proposed a Syntheticmentioning

confidence: 99%

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Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Cyrta

Augspach

Filippo

et al. 2020

Preprint

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Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in ~10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data suggest a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

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“…Most recently, two studies demonstrated that SMARCA4 was required for growth of prostatic adenocarcinoma cells 69,75 , as also confirmed by our results (Fig. 2).…”

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Cyrta

Augspach

Filippo

et al. 2020

Preprint

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“…For example, the BRD protein BRG1, encoded by SMARCA4, is an ATPase subunit of the SWI/SNF complex that mobilizes nucleosomes (Griffin et al 2008, Medina & Sanchez-Cespedes 2008. Ding et al recently showed that increased BRG1 expression in PTEN-deficient PC cells led to chromatin remodeling into a configuration that drove a protumorigenic transcriptome (Ding et al 2019). They employed ATAC-seq in PTEN-deficient 22Rv1 PC cells to show that BRG1 knockdown led to a 60% reduction in open chromatin regions compared to BRG1-intact cells (Ding et al 2019).…”

Section: Bromodomain-containing Proteins and Chromatin Reprogramming mentioning

confidence: 99%

“…Ding et al recently showed that increased BRG1 expression in PTEN-deficient PC cells led to chromatin remodeling into a configuration that drove a protumorigenic transcriptome (Ding et al 2019). They employed ATAC-seq in PTEN-deficient 22Rv1 PC cells to show that BRG1 knockdown led to a 60% reduction in open chromatin regions compared to BRG1-intact cells (Ding et al 2019). They also showed that high BRG1 expression was associated with worse outcomes in PC patients with low PTEN expression (Ding et al 2019).…”

Section: Bromodomain-containing Proteins and Chromatin Reprogramming mentioning

confidence: 99%

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Braadland

Urbanucci

2019

Endocrine-Related Cancer

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Tumor evolution is based on the ability to constantly mutate and activate different pathways under the selective pressure of targeted therapies. Epigenetic alterations including those of the chromatin structure are associated with tumor initiation, progression and drug resistance. Many cancers, including prostate cancer, present enlarged nuclei, and chromatin appears altered and irregular. These phenotypic changes are likely to result from epigenetic dysregulation. High-throughput sequencing applied to bulk samples and now to single cells has made it possible to study these processes in unprecedented detail. It is therefore timely to review the impact of chromatin relaxation and increased DNA accessibility on prostate cancer growth and drug resistance, and their effects on gene expression. In particular, we focus on the contribution of chromatinassociated proteins such as the bromodomain-containing proteins to chromatin relaxation. We discuss the consequence of this for androgen receptor transcriptional activity and briefly summarize wider gain-of-function effects on other oncogenic transcription factors and implications for more effective prostate cancer treatment.

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Landscapes of synchronous multiple primary cancers detected by next‐generation sequencing

Kong

Lin

et al. 2022

FEBS Open Bio

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An increase in the detection rate of multiple primary cancers has been accompanied with declining cancer death rates over the past few decades. However, synchronous multiple primary tumors have gradually increased, and the molecular mechanisms involved in the synchronous occurrence of multiple primary cancers of different origins are unclear. To investigate these mechanisms, we sequenced cancer tissues by FoundationOne CDx. Data were annotated with annovar, and we then performed pathway enrichment analysis. A total of 109 genes that were mutated in all samples were clustered into different diseases, biological processes, and molecular functions. GO and KEGG analyses indicated that the P53 and PKB signaling pathways may be relevant to the occurrence of synchronous multiple primary cancers. In summary, patients with a concordance of mutations in pathogenetic genes may have a higher risk of developing a second cancer. Our research may provide a basis for the development of individualized treatments for synchronous multiple primary cancers.

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Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer

Abstract: that BRG1 inhibition is a promising approach against PTENmutant prostate tumors in preclinical models.

Cited by 60 publications

References 66 publications

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

Landscapes of synchronous multiple primary cancers detected by next‐generation sequencing

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