LncRNA MALAT1 promotes development of mantle cell lymphoma by associating with EZH2

Abstract

BackgroundMantle cell lymphoma (MCL) is considered an aggressive subtype of non-Hodgkin’s lymphoma with variable treatment responses. There is an urgent need to identify novel markers with prognostic and therapeutic value for MCL. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancers, including MCL. Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a lncRNA located at pathognomonic translocation site of t (11; 14) of MCL. MALAT1 is known to be overexpressed in solid tumors and hematologic malignancies. However, the pathological role and clinical relevance of MALAT1 in MCL are not completely understood.MethodsWe quantified MALAT1 in MCL samples (40) and CD19+ B cells by quantitative real time polymerase chain reaction (qRT-PCR) and correlated levels with clinical outcome. We silenced MALAT1 in MCL cell lines and analyzed cells in tumorigenic assays and formation of transcription complexes.ResultsWe found that the expression of MALAT1 was elevated in human MCL tumors and cell lines as compared to normal controls, and the elevated levels of MALAT1 correlated with higher MCL international prognostic index (MIPI) and reduced overall survival. MCL with knockdown of MALAT1 showed impaired cell proliferation, facilitated apoptosis and produced fewer clonogenic foci. The increased expression of p21 and p27 upon MALAT1 knockdown was regulated by enhancer of zeste homolog 2 (EZH2). Moreover, decreased phosphorylation of EZH2 at T350 attenuated the binding to MALAT1.ConclusionsOur findings illuminate the oncogenic role of MALAT1, which may serve as a novel biomarker and as a therapeutic target in MCL.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1100-9) contains supplementary material, which is available to authorized users.

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

“…Moreover, EZH2 phosphorylation by JAK3 in NKTL, as we reported previously, functionally switch the role of EZH2 from PRC2-associated epigenetic repressor to PRC2-independent transcriptional activator [69]. CDK1-mediated EZH2 phosphorylation, initially demonstrated as a key mechanism that regulates cell cycle and differentiation in embryonic stem cells [98][99][100], is crucial for EZH2 binding to tumorigenic HOTAIR [98] and MALAT1 [90].…”

“…MALAT1, another EZH2-binding lncRNA, regulates cancer cell metastasis [85][86][87][88] and chemo-resistance [89] in different solid tumors via EZH2-associated mechanisms. In mantle cell lymphoma, elevated MALAT1 expression correlates with poor prognosis and reduces overall survival, and knockdown of MALAT1 results in an enhanced level of P21 and P27 through the modulation of EZH2 [90]. In T and NK cell lymphoma, the EZH2-binding MALAT1 is highly expressed and linked to poor prognosis [91].…”

Long non‑coding RNA NNT‑AS1 contributes to cell proliferation, metastasis and apoptosis in human ovarian cancer

“…LncRNAs are primarily transcriptionally regulated by RNA polymerase II and serve a significant function in various process, including the splicing of introns, 5'-end capping and 3'-end polyadenylation (8), and have been demonstrated to affect histone modifications, binding of transcription factors to targeted genes and chromatin remodeling (9). LncRNAs have been indicated to affect cancer cell proliferation (10), metastasis (11), apoptosis (12) and autophagy (13) in a number of types of malignancy.…”

Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution

“…isoform [58]. MALAT1, which also functions as oncogene transcript being involved in diverse cancer types [59,60], was proposed to modulate the phosphorylation status of SR proteins in the nucleus, including the MALAT1-interacting SRSF1 [61]. While phosphorylated SRSF1 is accumulated in nuclear speckles (NS), SRSF1 dephosphorylation is crucial for the export of mRNA-associated proteins and promotes the interaction with cytoplasmic mRNAs, likely affecting translation [62,63].…”