Gene Silencing Associated with SWI/SNF Complex Loss during NSCLC Development

Song, Shujie; Walter, Vonn; Karaca, Mehmet; Liu, Ying; Bartlett, Christopher S.; Smiraglia, Dominic J.; Serber, Daniel; Sproul, Christopher D.; Plass, Christoph; Zhang, Jiren; Hayes, D. Neil; Zheng, Yanfang; Weissman, Bernard E.

doi:10.1158/1541-7786.mcr-13-0427

Cited by 24 publications

(13 citation statements)

References 65 publications

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“…Recent sequencing efforts have shown silence of BRG1 in multiple primary NSCLC clinical specimens and human lung tumor cell lines. 31 In this study, BRG1 was confirmed to be significantly expressed at low levels in lung cancer tissues and cells. Furthermore, we validated that overexpression of BRG1 inhibited proliferation and metastasis of lung cancer cells and suppressed growth of xenografts in nude mice.…”

Section: Discussionmentioning

confidence: 51%

Restoration of BRG1 inhibits proliferation and metastasis of lung cancer by regulating tumor suppressor miR-148b

Zhou

2015

OTT

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BackgroundBrahma-related gene 1 (BRG1) has been implicated in a variety of biological processes, and it has been found to be mutated or silenced in numerous cancers, including lung cancer. Recent reports have proposed BRG1 as a tumor suppressor, but its roles in cell proliferation and metastasis remain unknown. miR-148b functions as a tumor suppressor in non-small-cell lung cancer. However, the mechanism responsible for the downregulation of miR-148b in lung cancer is still elusive.MethodsThe expression of BRG1 and miR-148b was evaluated in lung cancer tissues and cells using quantitative real-time polymerase chain reaction. The effect of BRG1 on proliferation of lung cancer cells was investigated using MTT assay. Transwell and Western blot assays were used to analyze the effect of BRG1 on invasion and epithelial–mesenchymal transition (EMT), respectively. The target of miR-148b was ascertained using luciferase reporter assay. Chromatin immunoprecipitation (ChIP) assay was performed to analyze the relation of BRG1 and the promoter region of miR-148b.ResultsRestoration of BRG1 was demonstrated to inhibit cell proliferation, metastasis, and EMT in lung cancer cell lines. Furthermore, we found that miR-148b was positively regulated by BRG1. Additionally, we suggested that miR-148b suppressed cell proliferation, metastasis, and EMT in lung cancer cells by directly binging to 3′-untranslated region of WNT1, blocking the WNT1/β-catenin signaling pathway. ChIP assay showed that BRG1 bound to the promoter of miR-148b in A549 cells.ConclusionBRG1 positively regulated the expression of miR-148b, leading to inhibition of cell proliferation, metastasis, restraint of EMT, and inactivation of the WNT/β-catenin signaling pathway, which highlights potential therapeutic possibilities for the treatment of lung cancer.

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Section: Discussionmentioning

confidence: 51%

Restoration of BRG1 inhibits proliferation and metastasis of lung cancer by regulating tumor suppressor miR-148b

Zhou

2015

OTT

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“…SMARCA4/BRG1 is an ATP-dependent catalytic subunit of the SWI/SNF chromatin remodelling complex, best known for its role in malignant rhabdoid tumors. Loss of SMARC4 has been reported in 5% to 20% of NSCLC, leading to epigenetic silencing of downstream genes, independent of DNA methylation (91,92). Interestingly, SMARCA4 deficient tumors are typically EGFR wild type and TTF-1 negative (93), suggesting that SMARCA4 loss could be a bone fide oncogenic driver event.…”

Section: Histone Modification and Chromatin Organizationmentioning

confidence: 99%

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer

et al. 2017

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The advent of targeted therapies has established new standards of care for defined molecular subsets of non-small cell lung cancer (NSCLC). Not only has this led to significant changes in the routine clinical management of lung cancer e.g., multiplexed genomic testing, but it has provided important principles and benchmarks for determining "actionability". At present, the clinical paradigms are most evolved for EGFR mutations and ALK rearrangements, where multiple randomized phase III trials have determined optimal treatment strategies in both treatment naïve and resistant settings. However, this may not always be feasible with low prevalence alterations e.g., ROS1 and BRAF mutations. Another emerging observation is that not all targets are equally "actionable", necessitating a rigorous preclinical, clinical and translational framework to prosecute new targets and drug candidates. In this review, we will cover the role of targeted therapies for NSCLC harbouring BRAF, MET, HER2 and RET alterations, all of which have shown promise in non-squamous non-small cell lung cancer (ns-NSCLC). We further review some early epigenetic targets in NSCLC, an area of emerging interest. With increased molecular segmentation of lung cancer, we discuss the upcoming challenges in drug development and implementation of precision oncology approaches, especially in light of the complex and rapidly evolving therapeutic landscape.

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“…In addition to rare cancers such as clear cell RCC, glioblastoma multiforme and pancreatic cancers, which are significantly associated with inactivating mutations of SETD2 , a significant frequency of SETD2 alterations is observed in several more common tumors (Figure 1), including melanoma (11), bladder and lung cancer (cbioportal), which also exhibit alterations in other chromatin modifiers such as the SWI/SNF complex SMARCA4 ATP-ase subunit (12). …”

Section: Setd2 In Cancermentioning

confidence: 99%

A New Chromatin–Cytoskeleton Link in Cancer

Giaccia

2016

Molecular Cancer Research

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The set domain containing 2 (SETD2) histone methyltransferase, located at 3p2, specifically trimethylates lysine 36 of histone H3 (H3K36me3). H3K36me3 is an active mark involved in transcriptional elongation and RNA processing, and a key regulator of DNA repair. In fact, SETD2 is the only methyltransferase that “writes” the H3K36me3 mark. Recent results from Park et al have found a new role for SETD2 in the methylation of K40 of α-tubulin. Loss of SETD2 abolishes methylation of K40 of α-tubulin, and results in a dysfunctional mitotic spindle and abnormalities in cytokinesis. Thus, SETD2 links chromatin and cytoskeleton homeostasis through its methyltransferase activity. These studies have important implications on the role of SETD2 mutations in promoting genomic instability and tumor progression.

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Gene Silencing Associated with SWI/SNF Complex Loss during NSCLC Development

Cited by 24 publications

References 65 publications

Restoration of BRG1 inhibits proliferation and metastasis of lung cancer by regulating tumor suppressor miR-148b

Restoration of BRG1 inhibits proliferation and metastasis of lung cancer by regulating tumor suppressor miR-148b

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer

A New Chromatin–Cytoskeleton Link in Cancer

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