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

Christos Demosthenous,Jing Sun,Shiv K Gupta,Mamta Gupta,Tammy P Troska,Yongsen Wang

doi:10.3389/fonc.2020.01226

Christos Demosthenous, Jing Sun + Show 4 more

Open Access

https://doi.org/10.3389/fonc.2020.01226

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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 (EZH2Δ550−738 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.

Highlights

Mantle cell lymphoma (MCL) is an aggressive form of B cell lymphoma, which accounts for ∼6% of all non-Hodgkin lymphomas (NHL) [1, 2]
The global level of H3K27trimethylation in the lymphoma cell lines was more or less similar to that of normal B cells (Supplementary Figure S1). These results indicate that the levels of enhancer of zeste homolog 2 (EZH2), SUZ12, and EED (PRC2 components) are upregulated in lymphoma cells as compared to normal B cells, but this is not the case for global levels of H3K27 tri-methylation
Histone methyltransferase EZH2 is the catalytic subunit of polycomb repressive complex 2 (PRC2), and the tyrosine 641 (Y641) of EZH2 is the most frequently mutated residue, up to 22% of germinal center-derived lymphomas and 24% of FL acquiring mutations at this site [16, 17]

Summary

Introduction

Mantle cell lymphoma (MCL) is an aggressive form of B cell lymphoma, which accounts for ∼6% of all non-Hodgkin lymphomas (NHL) [1, 2]. Patients do relapse, often with emergence of drug resistance, which remains a critical barrier to the current treatment. Identifying alternative approaches to overcome drug resistance in the relapsed MCL is an urgent unmet medical need. Polycomb repressive complex 2 (PRC2), is an important epigenetic regulator that comprises three main components: enhancer of zeste homolog 2 (EZH2), zinc fingercontaining SUZ12 and WD40-repeat protein EED. EZH2 gains histone methyltransferase activity only when it complexes with other 2 subunits, EED and SUZ12 to form PRC2 [6,7,8,9]

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