Epigenetic Antagonism between Polycomb and SWI/SNF Complexes during Oncogenic Transformation

Wilson, Barbara G.; Wang, Xi; Shen, Xiaohua; McKenna, Elizabeth S.; Lemieux, Madeleine E.; Cho, Yoon Jae; Koellhoffer, Edward C.; Pomeroy, Scott L.; Orkin, Stuart H.; Roberts, Charles W.M.

doi:10.1016/j.ccr.2010.09.006

Cited by 556 publications

(483 citation statements)

References 51 publications

(102 reference statements)

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“…However, more recently, engineered mouse models showed that SMARCB1 haploinsufficiency cooperates with both RB and TP53 haploinsufficiency to increase penetrance and reduce latency of tumor onset (9,22,37) and in vitro studies showed that SMARCB1 inactivation globally affects the epigenetic status of the cancer genome (38,39). We observed that VAESBJ cells retain a wild-type TP53 but carry a homozygous deletion of CDKN2A locus, thus displaying impaired p16/RB and p14/TP53 responses.…”

Section: Discussionmentioning

confidence: 79%

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

Brenca

Rossi

Lorenzetto

et al. 2013

Molecular Cancer Therapeutics

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Epithelioid sarcoma is a rare soft tissue neoplasm that usually arises in the distal extremities of young adults. Epithelioid sarcoma presents a high rate of recurrences and metastases and frequently poses diagnostic dilemmas. We previously reported loss of tumor suppressor SMARCB1 protein expression and SMARCB1 gene deletion in the majority of epithelioid sarcoma cases. Unfortunately, no appropriate preclinical models of such genetic alteration in epithelioid sarcoma are available. In the present report, we identified lack of SMARCB1 protein due to a homozygous deletion of exon 1 and upstream regulatory region in epithelioid sarcoma cell line VAESBJ. Restoration of SMARCB1 expression significantly affected VAESBJ cell proliferation, anchorage-independent growth, and cell migration properties, thus supporting the causative role of SMARCB1 loss in epithelioid sarcoma pathogenesis. We investigated the translational relevance of this genetic background in epithelioid sarcoma and showed that SMARCB1 ectopic expression significantly augmented VAESBJ sensitivity to gamma irradiation and acted synergistically with flavopiridol treatment. In VAESBJ, both activated ERBB1/EGFR and HGFR/MET impinged on AKT and ERK phosphorylation. We showed a synergistic effect of combined inhibition of these 2 receptor tyrosine kinases using selective small-molecule inhibitors on cell proliferation. These observations provide definitive support to the role of SMARCB1 inactivation in the pathogenesis of epithelioid sarcoma and disclose novel clues to therapeutic approaches tailored to SMARCB1-negative epithelioid sarcoma.

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Section: Discussionmentioning

confidence: 79%

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

Brenca

Rossi

Lorenzetto

et al. 2013

Molecular Cancer Therapeutics

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“…A requirement for Ezh2 in malignant self-renewal in murine cancer models has been suggested, either using shRNA approaches (14) or genetically engineered ablation (30). In contrast, we provide evidence that Ezh2 is not strictly required for MLL-AF9 leukemia, as we were able to derive Ezh2-null MLL-AF9 AML up to the third round of serial transplantation.…”

Section: Discussionmentioning

confidence: 57%

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Neff

Sinha

Kluk

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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202

218

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A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML. epigenetics | mouse model | polycomb group proteins | myeloid-lymphoid leukemia protein P olycomb repressive complex 2 (PRC2) has been implicated in development and cancer (1, 2). PRC2 is composed of the core components embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and a SET-domain methyltransferase, either enhancer of zeste 2 (EZH2) or enhancer of zeste 1 (EZH1) (3). The PRC2 complex catalyzes the di-and trimethylation of lysine residue 27 of histone 3 (H3K27me3), a repressive chromatin mark (4). Overexpression of EZH2 has been correlated with prostate cancer progression (5). Follow-up studies have confirmed and expanded these results for other cancer types, mainly solid tumors. In the hematopoietic system, forced expression of Ezh2 increases serial transplantation potential in hematopoietic stem cells (6) and enhances transformation in a model of multiple myeloma (7). Intriguingly, heterozygous loss of function of EZH2 has been associated with adverse prognosis in myelofibrosis (8), and heterozygous and homozygous inactivation of EZH2 has been described in myelodysplastic syndromes and more recently in Tlineage lymphoblastic leukemia (9-12). In contrast, EZH2 alterations appear to be rare events in acute myeloid leukemia (AML). How to reconcile these findings on a mechanistic level is unclear. Given the heterogeneity of clinical samples, elucidating the complex role of PRC2 biology in cancer will be aided by studies in genetically defined animal models (13).Loss of function of PRC2 has been evaluated in several cancer models (14, 15). However, shRNA...

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“…59 Finally, recent evidence suggests that EZH2 may also have a role in rhabdoid tumors. 63,88 Inactivation of the chromatin remodeler SWI/SNF complex component SNF5 is highly prevalent in this disease. Targeted disruption of EZH2 also strongly impairs ATRT cell growth, suppresses tumor cell self-renewal, induces apoptosis, and potently sensitizes these cells to radiation.…”

Section: Kmts and Prmtsmentioning

confidence: 99%

“…61 The SNF5 gene encodes a subunit of ATP-dependent SWI/SNF chromatin remodeling complexes, 62 and complexes oppose epigenetic silencing by PRC2. 63 Loss of SNF5 tumor suppressor activity leads to elevated expression of the Polycomb gene EZH2, and polycomb targets are broadly methylated at H3K27 and repressed in ATRT. 63 In addition, the SNF5 protein has a role in histone acetylation.…”

Section: Ependymomamentioning

confidence: 99%

“…63 Loss of SNF5 tumor suppressor activity leads to elevated expression of the Polycomb gene EZH2, and polycomb targets are broadly methylated at H3K27 and repressed in ATRT. 63 In addition, the SNF5 protein has a role in histone acetylation. 64,65 Inhibition of histone deacetylases (HDACs) has been found to specifically restore normal expression of proteins involved in cell cycle, originally altered in ATRT cells, through promoter histone H3 and H4 acetylation, recapitulating the effect of SNF5 restoration in ATRT cells.…”

Section: Ependymomamentioning

confidence: 99%

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Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

Maury

Hashizume

2017

Epigenetics

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Malignancies are characterized by the reprogramming of epigenetic patterns. This reprogramming includes gains or losses in DNA methylation and disruption of normal patterns of covalent histone modifications, which are associated with changes in chromatin remodeling processes. This review will focus on the mechanisms underlying this reprogramming and, specifically, on the role of histone modification in chromatin machinery and the modifications in epigenetic processes occurring in brain cancer, with a specific focus on epigenetic therapies for pediatric brain tumors.

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Epigenetic Antagonism between Polycomb and SWI/SNF Complexes during Oncogenic Transformation

Cited by 556 publications

References 51 publications

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

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