The chromatin-remodeling enzyme BRG1 promotes colon cancer progression via positive regulation of WNT3A

Lin, Shengtao; Jiang, Tao; Ye, Ling; Han, Ziqiang; Liu, Yuan; Liu, Chenchen; Yuan, Chenwei; Zhao, Senlin; Chen, Jian; Wang, Jingtao; Tang, Huamei; Lu, Su; Yang, Liguang; Wang, Xiaoliang; Yan, Dongwang; Peng, Zhihai; Fan, Junwei

doi:10.18632/oncotarget.13326

Cited by 24 publications

(26 citation statements)

References 38 publications

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“…6 ). ALDOA is a glycolytic enzyme observed to accumulate in CRC 38 , COPS6 is a subunit of the COP9 signalosome specifically required to drive CRC 39 – 41 , MCM2 functions as a DNA replication licensing factor needed to override once-per-cycle DNA replication in S-phase 42 , 43 and SMARCA4 (BRG1) is a SWI/SNF component activating WNT and VEGF signaling to drive CRC 31 , 44 , 45 . While HLA peptides from these four proteins were reliably detected on normal colon organoids, these were consistently absent from the ligandome of all four CRC organoid lines, suggesting that these proteins may be functionally important in CRC and therefore preserved from degradation (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell derived tumor organoids display diversity in HLA class I peptide presentation

et al. 2020

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Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15–25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.

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Section: Resultsmentioning

confidence: 99%

Single-cell derived tumor organoids display diversity in HLA class I peptide presentation

et al. 2020

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“…This finding provides additional evidence that elevated BRG1 expression, not BRG1 mutation, is a marker for poor prognosis in an increasing number of cancer types. Prior work has demonstrated that high BRG1 mRNA expression inversely correlates with patient survival in breast cancer (27,28,39), colorectal cancer (62,63), and neuroblastoma (29). In addition, BRG1 is required for various aspects of cancer cell survival, proliferation, and function in HeLa cells (64), leukemia cells (65,66), breast cancer (33,43), hepatocarcinoma (67), colorectal cancer (68), neuroblastoma (29), melanoma (30,69,70), and certain medullablastoma tumors (71).…”

Section: Discussionmentioning

confidence: 99%

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

Muthuswami

Bailey

Radhakrishnan

et al. 2018

Preprint

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BRG1 is one of two mutually exclusive ATPases that function as the catalytic subunit of human SWI/SNF chromatin remodeling enzymes. BRG1 has been identified as a tumor suppressor in some cancer types but has been shown to be expressed at elevated levels, relative to normal tissue, in other cancers. Using the TCGA (The Cancer Genome Atlas) prostate cancer database, we determined that BRG1 mRNA and protein expression is elevated in prostate tumors relative to normal prostate tissue. Only 3 of 491 (0.6%) sequenced tumors showed amplification of the locus or mutation in the protein coding sequence, arguing against the idea that elevated expression due to amplification or expression of a mutant BRG1 protein is associated with prostate cancer. Kaplan-Meier survival curves showed that BRG1 expression in prostate tumors inversely correlated with survival. However, BRG1 expression did not correlate with Gleason score/ISUP Grade Group, indicating it is an independent predictor of tumor progression/patient outcome. To experimentally assess BRG1 as a possible therapeutic target, we treated prostate cancer cells with a biologic inhibitor called ADAADi that targets the activity of the SNF2 family of ATPases in biochemical assays but showed specificity for BRG1 in prior tissue culture experiments. The inhibitor decreased prostate cancer cell proliferation and induced apoptosis.When directly injected into xenografts established by injection of prostate cancer cells in mouse flanks, the inhibitor decreased tumor growth and increased survival. These results indicate the efficacy of pursuing BRG1 as both an indicator of patient outcome and as a therapeutic target.

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“…In a clinical analysis of colon cancer, BRG1 expression levels were positively correlated with cancer progression and negatively correlated with patient survival. Reduction of BRG1 levels resulted in reduced cell proliferation in culture and reduced tumor growth in orthotopic transplants [ 99 ]. Prior studies had implicated WNT3A as a regulator of colon cancer cells [ 100 ].…”

Section: Brg1 Is Expressed At Elevated Levels In Other Tumor Typesmentioning

confidence: 99%

The BRG1 ATPase of Human SWI/SNF Chromatin Remodeling Enzymes as a Driver of Cancer

et al. 2017

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Mammalian SWI/SNF enzymes are ATP-dependent remodelers of chromatin structure. These multisubunit enzymes are heterogeneous in composition; there are two catalytic ATPase subunits, BRM and BRG1, that are mutually exclusive, and additional subunits are incorporated in a combinatorial manner. Recent findings indicate that approximately 20% of human cancers contain mutations in SWI/SNF enzyme subunits, leading to the conclusion that the enzyme subunits are critical tumor suppressors. However, overexpression of specific subunits without apparent mutation is emerging as an alternative mechanism by which cellular transformation may occur. Here we highlight recent evidence linking elevated expression of the BRG1 ATPase to tissue-specific cancers and work suggesting that inhibiting BRG1 may be an effective therapeutic strategy.

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The chromatin-remodeling enzyme BRG1 promotes colon cancer progression via positive regulation of WNT3A

Cited by 24 publications

References 38 publications

Single-cell derived tumor organoids display diversity in HLA class I peptide presentation

Single-cell derived tumor organoids display diversity in HLA class I peptide presentation

BRG1 is a prognostic indicator and a potential therapeutic target for prostate cancer

The BRG1 ATPase of Human SWI/SNF Chromatin Remodeling Enzymes as a Driver of Cancer

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