Abstract
Long noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N6-methyladenosine (m6A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m6A-modified lncRNA in diffuse large B cell lymphoma (DLBCL) has remained poorly defined. In the present study, we showed that lncRNA TRERNA1 was associated with the poor prognosis of DLBCL patients. TRERNA1 with internal m6A modification was highly correlated with the demethylase ALKBH5 expression. We further demonstrated that TRERNA1 was a potential downstream target of ALKBH5-mediated m6A modification by m6A-RNA sequencing and m6A-RIP assays. Decreased m6A methylation of TRERNA1 regulated by ALKBH5 was shown to regulate cell proliferation in vitro and in vivo. The results of mechanism analyses revealed that TRERNA1 recruited EZH2 to epigenetically silence the expression of the cyclin-dependent kinases inhibitor p21 by H3K27me3 modification of its promoter region. In addition, ALKBH5 further inhibited p21 expression. Taken together, our results elucidate the functional roles and epigenetic alterations of TRERNA1 through m6A modification in DLBCL. TRERNA1, the expression of which is upregulated by ALKBH5, acts as a scaffold that decreases p21 expression. The results of the present study provide novel targets for the diagnosis and treatment of DLBCL.
Highlights
Diffuse large B cell lymphoma (DLBCL) is one of the most common hematologic malignancies and exhibits a striking degree of genetic heterogeneity worldwide [1]
We showed that Long noncoding RNAs (lncRNAs) Translational regulatory lncRNA 1 (TRERNA1) was associated with the poor prognosis of DLBCL patients
Numerous epigenetic modifiers have been used for the clinical treatment of patients with hematologic malignancies, including inhibitors of DNA methyltransferases (DNMTs), enhancers of zeste homolog 2 (EZH2), histone deacetylases (HDACs), and isocitrate dehydrogenases (IDHs) [4]
Summary
Diffuse large B cell lymphoma (DLBCL) is one of the most common hematologic malignancies and exhibits a striking degree of genetic heterogeneity worldwide [1]. Translational regulatory lncRNA 1 (TRERNA1) was first reported as an enhancer-like RNA in mediating the expression of its neighboring genes [11]. N6-methyladenosine (m6A), the most prevalent RNA methylation modification, regulates gene expression by altering RNA splicing, editing, stability, degradation, and lncRNA/circular RNA activity [7, 15,16,17]. Increasing evidence has shown that m6A modification significantly affects the pathogenesis of multiple cancers, with recent studies, have shown that m6A mRNA methylation plays an important role in regulating T cell homeostasis and the carcinogenesis of acute myeloid leukemia [18, 19]. Our results reveal the important role of TRERNA1 in DLBCL and show that m6A modification of this lncRNA may serve as a promising marker of this disease.
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