The c-Myc-regulated lncRNA NEAT1 and paraspeckles modulate imatinib-induced apoptosis in CML cells

Abstract

Chronic myeloid leukemia (CML) is a clonal disease characterized by the presence of the constitutively active tyrosine kinase BCR-ABL oncoprotein. Although BCR-ABL is crucially important for pathogenesis and treatment response, it is thought that some additional factors might be involved in the regulation of these processes. Aberrant expression of long noncoding RNAs (lncRNAs) has recently been identified to be involved in various diseases including cancer, suggesting that lncRNAs may play a role in BCR-ABL-mediated CML. In this study, we found that nuclear-enriched abundant transcript 1 (NEAT1), a lncRNA essential for the formation of nuclear body paraspeckles, is significantly repressed in primary CML cells. NEAT1 expression could be restored by inhibiting BCR-ABL expression or its kinase activity in K562 cells. We also demonstrated that NEAT1 is regulated by c-Myc. Knockdown of NEAT1 could promote imatinib (IM)-induced apoptosis, and we demonstrated that the NEAT1-binding paraspeckle protein splicing factor proline/glutamine-rich (SFPQ) is required for NEAT1-mediated apoptosis in K562 cells. RNA-seq analysis revealed that SFPQ regulates cell growth and death pathway-related genes, confirming its function in IM-induced apoptosis. Collectively, these results assign a biological function to the NEAT1 lncRNA in CML apoptosis and may lead to fuller understanding of the molecular events leading to CML.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0884-z) contains supplementary material, which is available to authorized users.

MYC-regulated lncRNA NEAT1 promotes B cell proliferation and lymphomagenesis via the miR-34b-5p-GLI1 pathway in diffuse large B-cell lymphoma

“…The results were also validated by dualluciferase reporter and RIP assays, indicating that the NEAT1-miR-34b-5p-GLI1 axis exerted a vital effect on DLBCL progression. MYC has been shown to bind to the promoter of NEAT1, and suppression of NEAT1 expression regulates cell apoptosis in chronic myeloid leukaemia (CML) [27]. GLI1 inhibition has been reported to repress cell growth and cell cycle progression and promote apoptosis in human chondrosarcoma cells [9].…”

“…A previous study suggested that MYC can bind directly to the lncRNA NEAT1 promoter, reducing its expression to promote cell apoptosis in chronic myeloid leukaemia (CML) [27]. Moreover, the binding sites of MYC in the NEAT1 promoter region were predicted by bioinformatics analysis using JASPAR (http://jaspa r.gener eg.net/).…”

“…Recently, it was shown that the Smurf2-YY1 axis regulates MYC expression to reduce B cell proliferation [26]. In addition, MYC can bind to NEAT1 and inhibit its expression to regulate cell apoptosis in chronic myeloid leukaemia (CML) [27]. Thus, we predicted that MYC could bind to the promoter of NEAT1 by JASPAR analysis and modulate the expression of NEAT1.…”

Long non-coding RNA NEAT1/miR-338-3p axis impedes the progression of acute myeloid leukemia via regulating CREBRF

“…And NEAT1 impeded the progression of osteoarthritis via the regulation of miR-181a-GPD1L axis [33]. Additionally, Zeng et al attested that NEAT1 exacerbated cell apoptosis in chronic myeloid leukemia (CML) [34]. A recent report demonstrated that NEAT1 could reduce cell proliferation and evoke cell apoptosis of AML cells [35].…”

LncRNA NEAT1 Targets Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via the miR-410-3p/YY1 Axis

“…LncRNA-miRNA-mRNA interactions are pivotal in various biological phenomena in oncology and immunology wherein lncRNAs have been shown to function as miRNA sponges ( 11 , 12 ). Recent studies have demonstrated that the lncRNA NEAT1 (nuclear enriched abundant transcript 1) is an oncogene that is overexpressed in multiple malignancies, including colorectal cancer ( 13 ), breast cancer ( 14 ), and leukemia ( 15 ). Shui et al reported the upregulation of NEAT1 in peripheral blood mononuclear and Th17 cells in patients with RA and during the CD4+ T cells differentiation ( 16 ).…”