Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

Wassef, Michel; Rodilla, Verónica; Teissandier, Aurélie; Zeitouni, Bruno; Gruel, Nadège; Sadacca, Benjamin; Irondelle, Marie; Charruel, Margaux; Ducos, Bertrand; Michaud, Audrey; Caron, Matthieu; Marangoni, Elisabetta; Chavrier, Philippe; Tourneau, Christophe Le; Kamal, Maud; Pasmant, Éric; Vidaud, Michel; Servant, Nicolas; Reyal, Fabien; Meseure, Dider; Vincent‐Salomon, Anne; Fre, Silvia; Margueron, Raphaël

doi:10.1101/gad.269522.115

Cited by 78 publications

(80 citation statements)

References 62 publications

(79 reference statements)

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“…S3E). This observation was expected, because it is consistent with a recent report showing that PRC2 inactivation favors breast tumorigenicity (17). Importantly, the reduced cell invasion upon EZH2 knockdown was effectively rescued with ectopic overexpression of FOXM1, but the H3K27me3 level remained depleted (Fig.…”

Section: Reciprocal Coregulation Of Ezh2 and Foxm1 Promotes Invasionsupporting

confidence: 79%

“…7B). In contrast, breast cancer patients with high expression of SUZ12 in their tumors had a significantly longer timeto-death; this finding is consistent with PRC2 having a tumor-suppressive role in breast cancer, as suggested in both our study and a recent report (17). Next, we investigated whether these oncogenic drivers correlated with patient distant metastasis-free survival (DMFS) in comparison with SUZ12.…”

Section: Pharmacological Inhibition Of Prc2 Promotes the Expression Osupporting

confidence: 63%

“…Furthermore, the inverse correlation between EZH2 and H3K27me3 levels seen in TNBC seems to indicate an impaired PRC2 activity in TNBC. Consistent with the clinical observation, a recent study has shown that deficient Ezh2/PRC2 activity is essential for TNBC tumorigenesis (17). Despite these findings in breast cancer, particularly in TNBC, the mechanism underlying the regulation of Ezh2 in relation to PRC2 activity or non-PRC2 activity is poorly understood.…”

supporting

confidence: 49%

“…The paradoxical role of EZH2 in tumorigenesis has been observed in several human cancers (16). Although its oncogenic role in promoting cancer progression has been well documented, in certain contexts it also can function as a tumor suppressor (17,20,(58)(59)(60)(61). In addition to leukemia, a tumor-suppressive role for EZH2 has been found in solid tumors such as pancreatic (61) and renal cancer (60).…”

Section: Discussionmentioning

confidence: 99%

“…The oncogenic function of Ezh2 has been linked to both PRC2-dependent and PRC2-independent activities (8)(9)(10)(11)(12)(13). Paradoxically, a context-dependent tumor-suppressive function of Ezh2 or PRC2 also has been reported in several malignancies (14)(15)(16)(17)(18). Moreover, high-grade breast, ovarian, and pancreatic cancers have been found to harbor low global H3K27me3, which is correlated with increased recurrence and poor survival (19)(20)(21).…”

mentioning

confidence: 99%

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HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara

Lee

Feng

et al. 2016

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

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Despite the established oncogenic function of Polycomb repressive complex 2 (PRC2) in human cancers, its role as a tumor suppressor is also evident; however, the mechanism underlying the regulation of the paradoxical functions of PRC2 in tumorigenesis is poorly understood. Here we show that hypoxia-inducible factor 1, α-subunit (HIFI-α) is a crucial modulator of PRC2 and enhancer of zeste 2 (EZH2) function in breast cancer. Interrogating the genomic expression of breast cancer indicates high HIF1A activity correlated with high EZH2 expression but low PRC2 activity in triple-negative breast cancer compared with other cancer subtypes. In the absence of HIFIA activation, PRC2 represses the expression of matrix metalloproteinase genes (MMPs) and invasion, whereas a discrete Ezh2 complexed with Forkhead box M1 (FoxM1) acts to promote the expression of MMPs. HIF1-α induction upon hypoxia results in PRC2 inactivation by selective suppression of the expression of suppressor of zeste 12 protein homolog (SUZ12) and embryonic ectoderm development (EED), leading to a functional switch toward Ezh2/FoxM1-dependent induction of the expression of MMPs and invasion. Our study suggests a tumor-suppressive function of PRC2, which is restricted by HIF1-α, and an oncogenic function of Ezh2, which cooperates with FoxM1 to promote invasion in triple-negative breast cancer.

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Section: Reciprocal Coregulation Of Ezh2 and Foxm1 Promotes Invasionsupporting

confidence: 79%

Section: Pharmacological Inhibition Of Prc2 Promotes the Expression Osupporting

confidence: 63%

supporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara

Lee

Feng

et al. 2016

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

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Cell Fate and Developmental Regulation Dynamics by Polycomb Proteins and 3D Genome Architecture

2019

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Targeted transitions in chromatin states at thousands of genes are essential drivers of eukaryotic development. Therefore, understanding the in vivo dynamics of epigenetic regulators is crucial for deciphering the mechanisms underpinning cell fate decisions. This review illustrates how, in addition to its cell memory function, the Polycomb group of transcriptional regulators orchestrates temporal, cell and tissue‐specific expression of master genes during development. These highly sophisticated developmental transitions are dependent on the context‐ and tissue‐specific assembly of the different types of Polycomb Group (PcG) complexes, which regulates their targeting and/or activities on chromatin. Here, an overview is provided of how PcG complexes function at multiple scales to regulate transcription, local chromatin environment, and higher order structures that support normal differentiation and are perturbed in tumorigenesis.

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BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska

Lukiyanchuk

Peitzsch

et al. 2019

Intl Journal of Cancer

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Prostate cancer (PCa) is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem-and nonstem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the polycomb repressive complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2-dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients' tumors and PCa cell lines, and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to an increase of aldehyde dehydrogenase (ALDH)-positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3-Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.

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Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

Cited by 78 publications

References 62 publications

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Cell Fate and Developmental Regulation Dynamics by Polycomb Proteins and 3D Genome Architecture

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

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