Deregulation of Polycomb Repressive Complex-2 in Mantle Cell Lymphoma Confers Growth Advantage by Epigenetic Suppression of cdkn2b

Abstract

The polycomb repressive complex 2 (PRC2) maintains the transcriptional repression of target genes through its catalytic component enhancer of zeste homolog 2 (EZH2). Through modulating critical gene expression, EZH2 also plays a role in cancer development and progression by promoting cancer cell survival and invasion. Mutations in EZH2 are prevalent in certain B-cell lymphoma subtypes such as diffuse large cell lymphoma and follicular lymphoma; while no EZH2 mutation has been reported in the mantle cell lymphoma (MCL). Here we demonstrate that the PRC2 components EZH2, EED and SUZ12 are upregulated in the MCL cells as compared to normal B-cells. Moreover, stably transfected cells with wild-type EZH2 or-EED showed increased cell growth and H3K27-trimehtylation. However, unlike wild-type EZH2, ectopic expression of a deletion construct of EZH2 (EZH2 550−738 lacking SET domain) had no growth advantage over control cells. Pharmacological inhibition of EZH2 suppressed H3K27me3 and had significant inhibitory effect on cell growth and colony forming capacity (p < 0.05) of MCL cells, and this effect was more or less comparable to the anti-proliferative effects of EZH2 inhibition in cells harboring EZH2-mutation. Mechanistically, EZH2 appears to downregulate expression of cdkn2b gene via enhanced H3K27me3, a well-known suppressive epigenetic mark, at the cdkn2b promoter region. Overall, these results highlight that deregulation of PRC2/EZH2 is associated with epigenetic suppression of cdkn2b in MCL, and in part responsible for increased cell growth, thus the EZH2 inhibitors may have therapeutic potential in the patients with MCL.

Downregulation of MEG3 and upregulation of EZH2 cooperatively promote neuroblastoma progression

“…Polycomb repressive complex 2 (PRC2) comprises EZH2, EED and SUZ12, among which, EZH2 is the only active subunit with a critical role. [17][18][19] The EZH2 catalytic SET domain catalysing histone 3 lysine 27 tri-methylation (H3K27me3) is reported to bind and silence specific tumour suppressor genes. 20,21 Earlier, Kamijo and co-workers demonstrated upregulation of EZH2 in NB in association with poorer prognosis and overall survival.…”

“…Polycomb repressive complex 2 (PRC2) comprises EZH2 , EED and SUZ12 , among which, EZH2 is the only active subunit with a critical role 17‐19 20,21 .…”

Migration and Adhesion of B-Lymphocytes to Specific Microenvironments in Mantle Cell Lymphoma: Interplay between Signaling Pathways and the Epigenetic Landscape

“…EZH2 mutation has not been identified in MCL patient samples or MCL cell lines [32,61], although PRC2/EZH2 complex overexpression has been reported in MCL cell lines [77,78]. The work of Demosthenous et al showed that deregulation of PRC2/EZH2 in MCL cell lines mediates epigenetic silencing of the CDKN2B CDK inhibitor gene to promote MCL cell proliferation and survival [77]. In addition, it has been shown that EZH2 overexpression in MCL cell lines and primary cells facilitates recruitment of the DNA methylation machinery, enabling more stable and long-term repression of HOX genes [78].…”

“…In addition to mutation, other genetic lesions affecting EZH2, including chromosomal gain or loss and DNA hypermethylation, have been identified in B-cell malignancies [100,117]. EZH2 mutation has not been identified in MCL patient samples or MCL cell lines [32,61], although PRC2/EZH2 complex overexpression has been reported in MCL cell lines [77,78]. The work of Demosthenous et al showed that deregulation of PRC2/EZH2 in MCL cell lines mediates epigenetic silencing of the CDKN2B CDK inhibitor gene to promote MCL cell proliferation and survival [77].…”

Mantle cell lymphoma management trends and novel agents: where are we going?

“…EZH2 gene mutations are uncommon in MCL, but a deregulated expression of EZH2 and chromodomain-containing proteins, such as EED and SUZ12, has been reported in MCL. 83 …”