Targeting BRD9 for Cancer Treatment: A New Strategy

Zhu, Xiuzuo; Liao, Yi; Tang, Liling

doi:10.2147/ott.s286867

Cited by 29 publications

(28 citation statements)

References 122 publications

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“…For Gleason scoring, both pathological methods and WHO classifications have changed during the collection of these data, which could affect the conclusions here, and is an unavoidable limitation in the use of publicly available retrospective cohorts. It has been shown that BRD9 is required for cell growth and its degradation prevents synovial sarcoma tumour progression [52,53]. Similar findings have been reported in hepatocellular carcinoma (HCC) with BRD9 overexpressed in HCC patients as well as promoting cell growth and metastasis, and its depletion and inhibition reducing these effects in HCC cells [54].…”

Section: Brd9 As a Biomarkersupporting

confidence: 61%

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BRD9 Expression, Alteration, Survival And Pathway Analysis In 11 Independent Prostate Cancer Cohorts

Barma¹,

Stone²,

Echeverría³

et al. 2021

Preprint

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Background and aims: Despite recent advances in advanced prostate cancer treatments, there are no clinically useful biomarkers or treatments for men with such cancers. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims to characterize BRD9, currently understudied in prostate cancer, and investigate its co-expression with other genes to assess its potential as a biomarker and therapeutic target in human prostate cancer. Materials and methods: Omics data from a total of 2053 prostate cancer patients across 11 independent datasets were accessed via Cancertool and cBioPortal. mRNA expression and co-expression, mutations, amplifications, and deletions were assessed with respect to key clinical parameters including survival, Gleason grade, stage, progression and treatment. Network and pathway analysis was carried out using Genemania, and heatmaps were constructed using Morpheus. Results: BRD9 is overexpressed in prostate cancer patients, especially those with metastatic disease. BRD9 expression did not differ in patients treated with second generation antiandrogens versus those who were not. BRD9 is co-expressed with many genes in the SWI/SNF and BET complexes, as well as those in common signaling pathways in prostate cancer. Summary and conclusions: BRD9 has potential as a diagnostic and prognostic biomarker in prostate cancer. BRD9 also shows promise as a therapeutic target, particularly in advanced prostate cancer, and as a co-target alongside other genes in the SWI/SNF and BET complexes, and those in common prostate cancer signalling pathways. These promising results highlight the need for wider experimental inhibition and co-targeted inhibition of BRD9 in vitro and in vivo, to build on the limited inhibition data available.

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Section: Brd9 As a Biomarkersupporting

confidence: 61%

“…plays an oncogenic role in many cancers with promise both as a diagnostic and prognostic biomarker [52][53][54]. The only paper on BRD9 and PCa used the TCGA evidence to show BRD9 worsened DFS, however did not investigate BRD9 as a biomarker in PCa [30].…”

Section: Brd9 As a Biomarkermentioning

confidence: 99%

BRD9 Expression, Alteration, Survival And Pathway Analysis In 11 Independent Prostate Cancer Cohorts

Barma¹,

Stone²,

Echeverría³

et al. 2021

Preprint

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show abstract

“…SWI/SNF subunits are the most commonly mutated chromatin-regulatory complexes in human cancer, mutated in 19.6% cancers, with subunits ARID1A , PBRM1 , SMARCA4 , and ARID2 already part of routine cancer diagnostics [ 15 , 58 ]. The literature suggests that BRD9 plays an oncogenic role in many cancers with promise both as a diagnostic and prognostic biomarker [ 32 , 33 , 36 ]. The only paper on BRD9 and PCa used the TCGA evidence to show that BRD9 worsened DFS but did not investigate BRD9 as a biomarker in PCa [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…BRD9 has been generating interest in the cancer research community in recent years, with data emerging in cancers such as squamous cell lung cancer, synovial sarcoma, and malignant rhabdoid tumours, where it has been shown to induce cancer hallmarks, correlate with aggression, and crucially, inhibition has led to anti-cancer effects [ 32 , 33 , 34 , 35 ]. However, despite this work in other cancers, BRD9 has not been well studied in PCa to date, with only one paper published in December 2020, which directly focused on BRD9 expression and inhibition in the disease [ 19 , 32 , 33 , 36 ]. This paper showed that BRD9 inhibition and knockdown have overlapping effects, reducing AR-positive cell line growth both in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Value of BRD9 as a Biomarker, Therapeutic Target and Co-Target in Prostate Cancer

et al. 2021

View full text Add to dashboard Cite

Background and aims: Despite recent advances in advanced prostate cancer treatments, clinical biomarkers or treatments for men with such cancers are imperfect. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims to characterise BRD9, currently understudied in prostate cancer, and investigate its co-expression with other genes to assess its potential as a biomarker and therapeutic target in human prostate cancer. Materials and methods: Omics data from a total of 2053 prostate cancer patients across 11 independent datasets were accessed via Cancertool and cBioPortal. mRNA M.expression and co-expression, mutations, amplifications, and deletions were assessed with respect to key clinical parameters including survival, Gleason grade, stage, progression, and treatment. Network and pathway analysis was carried out using Genemania, and heatmaps were constructed using Morpheus. Results: BRD9 is overexpressed in prostate cancer patients, especially those with metastatic disease. BRD9 expression did not differ in patients treated with second generation antiandrogens versus those who were not. BRD9 is co-expressed with many genes in the SWI/SNF and BET complexes, as well as those in common signalling pathways in prostate cancer. Summary and conclusions: BRD9 has potential as a diagnostic and prognostic biomarker in prostate cancer. BRD9 also shows promise as a therapeutic target, particularly in advanced prostate cancer, and as a co-target alongside other genes in the SWI/SNF and BET complexes, and those in common prostate cancer signalling pathways. These promising results highlight the need for wider experimental inhibition and co-targeted inhibition of BRD9 in vitro and in vivo, to build on the limited inhibition data available.

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“…Oncogenic mapping has revealed that these BRD-associated proteins are highly dysregulated in cancers [ 14 ]. However, many subunits still require further attention; among them, one of the largely unexplored subunits is the SWI/SNF complex of BRD9 (bromodomain-containing protein 9) [ 15 ]. The proteins that form a complex with bromodomain identify acetylated lysine residues on histones and are further responsible for promoting epigenetic changes in expression, such as transcription regulation, chromatin remodeling, and histone modification [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors

Sun

Zhao

et al. 2021

Cell Death Dis

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Gastrointestinal stromal tumors (GISTs) are primarily characterized by activating mutations of tyrosine kinase or platelet-derived growth factor receptor alpha. Although the revolutionary therapeutic outcomes of imatinib are well known, the long-term benefits of imatinib are still unclear. The effects of BRD9, a recently identified subunit of noncanonical BAF complex (ncBAF) chromatin remodeling complexes, in GISTs are not clear. In the current study, we evaluated the functional role of BRD9 in GIST progression. Our findings demonstrated that the expression of BRD9 was upregulated in GIST tissues. The downregulation or inhibition of BRD9 could significantly reduce cellular proliferation, and facilitates apoptosis in GISTs. BRD9 inhibition could promote PUMA-dependent apoptosis in GISTs and enhance imatinib activity in vitro and in vivo. BRD9 inhibition synergizes with imatinib in GISTs by inducing PUMA upregulation. Mechanism study revealed that BRD9 inhibition promotes PUMA induction via the TUFT1/AKT/GSK-3β/p65 axis. Furthermore, imatinib also upregulates PUMA by targeting AKT/GSK-3β/p65 axis. In conclusion, our results indicated that BRD9 plays a key role in the progression of GISTs. Inhibition of BRD9 is a novel therapeutic strategy in GISTs treated alone or in combination with imatinib.

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Targeting BRD9 for Cancer Treatment: A New Strategy

Cited by 29 publications

References 122 publications

BRD9 Expression, Alteration, Survival And Pathway Analysis In 11 Independent Prostate Cancer Cohorts

BRD9 Expression, Alteration, Survival And Pathway Analysis In 11 Independent Prostate Cancer Cohorts

Exploring the Value of BRD9 as a Biomarker, Therapeutic Target and Co-Target in Prostate Cancer

BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors

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