The FUS::DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma

Zullow, Hayley; Sankar, Akshay; Ingram, Davis R.; Guerra, Daniel Samé; D’Avino, Andrew R.; Collings, Clayton K.; Lazcano, Rossana; Wang, Wei‐Lien; Liang, Yu; Qi, Jun; Lazar, Alexander J.; Kadoch, Cigall

doi:10.1016/j.molcel.2022.03.019

Cited by 23 publications

(17 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It governs interactions between regulatory elements and transcription factors, underscoring its centrality in cellular homeostasis. Notably, disruptions in chromatin regulators have been linked to the initiation of malignancies, emphasizing the pivotal role of chromatin in cancer pathogenesis [12,27]. Consequently, chromatin regulators are plausible candidates for crucial involvement throughout tumorigenesis, progression, and metastatic dissemination.…”

Section: Discussionmentioning

confidence: 99%

Unravelling the complexity of kidney renal clear cell carcinoma prognosis: integrating chromatin regulators, gene signatures and associated immune landscapes

Wang,

Huang,

Chen

et al. 2023

Preprint

View full text Add to dashboard Cite

Background Kidney-renal clear cell carcinoma (KIRC) is the main subtype of renal cell carcinoma. KIRC exhibits significant resistance to conventional treatments, highlighting the need for pioneering therapeutic approaches. Within this framework, chromatin regulators (CRs) - proteins important for managing gene expression and orchestrating key biological processes - have been recognized as key players in the initiation and development of KIRC. Methods Utilizing the TCGA-KIRC dataset, we conducted differential gene analysis pertaining to chromatin regulators through application of the "limma" R package. We proceeded to establish and validate a prognostic model via LASSO Cox regression, with a particular emphasis on genes exerting substantial influence on KIRC prognosis. Our investigation was further extended to investigate the interrelationship between gene attributes, clinical parameters, the tumor microenvironment, and drug responsiveness. To enhance the predictive efficacy of our models, we harnessed advanced bioinformatics methodologies and techniques for visualizing protein interaction networks. Results Through the related studies, we found that the risk score obtained for CRs constituted an autonomous prognostic determinant in KIRC. Subsequently, a Nomogram prediction model was crafted that amalgamated clinical attributes with their corresponding risk evaluations. Ultimately, Polymerase chain reaction (PCR) was applied for comparative analysis of BRD9 expression levels in normal tissues and tumor specimens. Notably, the utilization of BRD9 marker-based constructs yielded significant predictive results. Conclusion We have introduced a novel prognostic framework for KIRC that seamlessly incorporates Chromatin Regulators. This innovative model exhibits substantial promise in enhancing the precision of prognostic forecasts for individuals afflicted with KIRC, thereby establishing a foundational platform for the refinement of therapeutic approaches.

show abstract

Section: Discussionmentioning

confidence: 99%

Unravelling the complexity of kidney renal clear cell carcinoma prognosis: integrating chromatin regulators, gene signatures and associated immune landscapes

Wang,

Huang,

Chen

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In a landmark study, the SS18-SSX fusion oncoprotein in synovial sarcoma was found to redirect (hijack) the aberrant SWI/SNF complex from enhancers to activate domains normally silenced by the PRC [93]. Further, a recent study showed that by sequestering the adipogenic transcription factor, CEBPB, FUS:: DDIT3 inhibits BAF (SWI/SNF) complex-mediated remodeling of adipogenic enhancer sites [94]. These are examples of the interesting and complex interplay between fusion oncoproteins and chromatin remodeling complexes, giving rise to a loss-of-function BAF complex phenotype in the absence of deleterious subunit mutations (e.g.…”

Section: Epigenetic Modifiers and Chromatin Remodeling Complexmentioning

confidence: 99%

The spectrum and significance of secondary (co‐occurring) genetic alterations in sarcomas: the hallmarks of sarcomagenesis

Dermawan

Rubin

2023

The Journal of Pathology

View full text Add to dashboard Cite

Bone and soft tissue tumors are generally classified into complex karyotype sarcomas versus those with recurrent genetic alterations, often in the form of gene fusions. In this review, we provide an overview of important co‐occurring genomic alterations, organized by biological mechanisms and covering a spectrum of genomic alteration types: mutations (single‐nucleotide variations or indels) in oncogenes or tumor suppressor genes, copy number alterations, transcriptomic signatures, genomic complexity indices (e.g. CINSARC), and complex genomic structural variants. We discuss the biological and prognostic roles of these so‐called secondary or co‐occurring alterations, arguing that recognition and detection of these alterations may be significant for our understanding and management of mesenchymal tumors. On a related note, we also discuss major recurrent alterations in so‐called complex karyotype sarcomas. These secondary alterations are essential to sarcomagenesis via a variety of mechanisms, such as inactivation of tumor suppressors, activation of proliferative signal transduction, telomere maintenance, and aberrant regulation of epigenomic/chromatin remodeling players. The use of comprehensive genomic profiling, including targeted next‐generation sequencing panels or whole‐exome sequencing, may be incorporated into clinical workflows to offer more comprehensive, potentially clinically actionable information. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

show abstract

“…Fusions between FUS or EWSR1 and DDIT3 are characteristic genetic abnormalities of myxoid liposarcoma, 76–78 and half of the cases show TERT promoter mutations 79 . Although the role of FUS::DDIT3 and EWSR1::DDIT3 remain to be clarified, recent studies have indicated that FUS::DDIT3 interacts with the SWI/SNF complex to modulate H3K27me3 distribution and to disrupt adipocytic differentiation 37,80 . Moreover, FUS::DDIT3 occupies super‐enhancers, and myxoid liposarcoma cells are sensitive to BET depletion that suppresses super‐enhancer activities 81 .…”

Section: Epigenetic Aberrations In Bone and Soft Tissue Sarcomas And ...mentioning

confidence: 99%

“…79 Although the role of FUS::DDIT3 and EWSR1::DDIT3 remain to be clarified, recent studies have indicated that FUS::DDIT3 interacts with the SWI/SNF complex to modulate H3K27me3 distribution and to disrupt adipocytic differentiation. 37,80 Moreover, FUS::DDIT3 occupies super-enhancers, and myxoid liposarcoma cells are sensitive to BET depletion that suppresses super-enhancer activities. 81 As a FET family fusion protein, FUS::DDIT3 forms phase-separated condensates in nuclei, resulting in the promotion of colocalization with BRD4.…”

Section: Epigenetic Aberrationsmentioning

confidence: 99%

Targeting epigenetic aberrations of sarcoma in CRISPR era

Tanaka

Nakamura

2023

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Sarcomas are rare malignancies that exhibit diverse biological, genetic, morphological, and clinical characteristics. Genetic alterations, such as gene fusions, mutations in transcriptional machinery components, histones, and DNA methylation regulatory molecules, play an essential role in sarcomagenesis. These mutations induce and/or cooperate with specific epigenetic aberrations required for the growth and maintenance of sarcomas. Appropriate mouse models have been developed to clarify the significance of genetic and epigenetic interactions in sarcomas. Studies using the mouse models for human sarcomas have demonstrated major advances in our understanding the developmental processes as well as tumor microenvironment of sarcomas. Recent technological progresses in epigenome editing will not only improve the studies using animal models but also provide a direct clue for epigenetic therapies. In this manuscript, we review important epigenetic aberrations in sarcomas and their representative mouse models, current methods of epigenetic editing using CRISPR/ dCas9 systems, and potential applications in sarcoma studies and therapeutics.

show abstract

The FUS::DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma

Cited by 23 publications

References 85 publications

Unravelling the complexity of kidney renal clear cell carcinoma prognosis: integrating chromatin regulators, gene signatures and associated immune landscapes

Unravelling the complexity of kidney renal clear cell carcinoma prognosis: integrating chromatin regulators, gene signatures and associated immune landscapes

The spectrum and significance of secondary (co‐occurring) genetic alterations in sarcomas: the hallmarks of sarcomagenesis

Targeting epigenetic aberrations of sarcoma in CRISPR era

Contact Info

Product

Resources

About