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LEF1-AS1, long non-coding RNA, inhibits proliferation in myeloid malignancy.

ABSTRACT: LEF1 antisense RNA 1 (LEF1-AS1) is an antisense long non-coding RNA encoded in the lymphoid enhancer-binding factor 1 (LEF1) locus. LEF1-AS1 is a conserved transcript dysregulated in hematopoiesis. This study aimed to functionally characterize the role of this transcript in myeloid malignancy and explore a possible regulatory effect of LEF1-AS1 upon LEF1. We show that LEF1-AS1 is highly expressed in normal hematopoietic stem cells but barely detectable in myeloid malignant cell lines. Additionally, bone marrow cells from myelodysplastic syndrome (n=12) and acute myeloid malignancy patients (n=28) expressed significantly reduced levels of LEF1-AS1 compared to healthy controls (n=15). Artificial LEF1-AS1 over-expression inhibited proliferation in HL60 and led to an upregulation of tumor suppressors p21 and p27, and reduced ERK1/2 activation. Unexpectedly, no underlying modulation of LEF1 was detected. Ectopic expression of LEF1-AS1 also inhibited proliferation in HELA, a cell line lacking endogenous expression of LEF1, supporting a LEF1-independent mechanism. Additionally, transient over-expression of LEF1-AS1 in AML patient cells also led to reduced proliferation and colony formation capacity. We used a mass spectrometry-based proteomics approach. Proteomic quantification identified the modulation of an important metabolic regulator, Fumarase, and concomitant accumulation of the metabolite fumarate.

SUBMITTER: Congrains-Castillo A

PROVIDER: S-EPMC6433713 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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LEF1-AS1, long non-coding RNA, inhibits proliferation in myeloid malignancy.

Congrains-Castillo Ada A Niemann Fernanda S FS Santos Duarte Adriana S AS Olalla-Saad Sara T ST

Journal of cellular and molecular medicine 20190215 4

LEF1 antisense RNA 1 (LEF1-AS1) is an antisense long non-coding RNA encoded in the lymphoid enhancer-binding factor 1 (LEF1) locus. LEF1-AS1 is a conserved transcript dysregulated in hematopoiesis. This study aimed to functionally characterize the role of this transcript in myeloid malignancy and explore a possible regulatory effect of LEF1-AS1 upon LEF1. We show that LEF1-AS1 is highly expressed in normal hematopoietic stem cells but barely detectable in myeloid malignant cell lines. Additional ...[more]

PMID: 30770626

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Project description:OBJECTIVES:The long-noncoding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes in glioblastoma (GBM) tissues. However, the expression pattern and biological function of lncRNAs remain largely unknown. Here, for the first time, the effects of lncRNA lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) on GBM progression both in vitro and in vivo are investigated. MATERIALS AND METHODS:Expression profiles of LEF1-AS1 in GBM specimens were investigated by bioinformatics analyses. LEF1-AS1 expression in GBM tissues was detected using a quantitative polymerase chain reaction. LEF1-AS1 expression was inhibited by transfecting the LEF1-AS1-specific small interfering RNAs (siRNAs) and stable cell lines established were inhibited by transfecting si-LEF1-AS1 viruses. The Cell Counting Kit-8, ethynyl deoxyuridine, and colony formation assay were used to examine proliferation function. The flow cytometry detected cell-cycle change and apoptosis. Migration effects were detected by a Transwell assay. The tumor xenografts and immunohistochemistry were performed to evaluate tumor growth in vivo. RESULTS:In this study, LEF1-AS1 expression was found significantly upregulated in GBM specimens compared with normal tissues. The 5-year overall survival in GBM patients from The Cancer Genome Atlas with high expression of LEF1-AS1 was inferior to that with low expression. It was confirmed that expression of LEF1-AS1 was higher in GBM tissues than normal ones. Knockdown of LEF1-AS1 significantly inhibited the malignancy of GBM cells, including proliferation and invasion, and promoted cell apoptosis. The result of Western blot assays indicated that knockdown of LEF1-AS1-mediated tumor suppression in GBM cells may be via the reduction of ERK and Akt/mTOR signaling activities. Finally, the in vivo experiment also demonstrated that knockdown LEF1-AS1 inhibited the growth-promoting effect of LEF1-AS1 of U87 cells. CONCLUSION:Our result indicated that lncRNA LEF1-AS1 acts as an oncogene in GBM and may be a pivotal target for this disease.

Project description:Recent evidence has proven that long noncoding RNAs (lncRNAs) play important roles in cancer biology, while few lncRNAs have been characterized in NSCLC. Here, we characterized a novel lncRNA, SBF2 antisense RNA 1 (SBF2-AS1), in non-small cell lung cancer (NSCLC).Quantitative real-time PCR was used to quantify SBF2-AS1 expression in NSCLC tissues and cell lines. The correlation of SBF2-AS1 expression with clinicopathologic features was analyzed in a cohort NSCLC patient. Loss of function and gain of function studies were performed to determine the effects of SBF2-AS1 on proliferation and metastasis of NSCLC cells. RNA immunoprecipitation and chromosome immunoprecipitation assay was performed to confirm the interaction between SBF2-AS1 with protein and chromosome.We confirmed that SBF2-AS1 was significantly upregulated in NSCLC compared with corresponding non-tumor tissues, and a high expression level of SBF2-AS1 was correlated with lymph node metastasis and advanced TNM stage. Using siRNAs specifically targeting SBF2-AS1 and plasmid vector, we successfully silenced and overexpressed SBF2-AS1 in NSCCLC cell lines and investigated its biological function both in vitro and in vivo. After the silencing of SBF2-AS1, the metastasis of NSCLC cells was significantly inhibited, the silencing of SBF2-AS1 decreased the proliferation of NSCLC cells, and the cell cycle was arrested at the G1 phase; while overexpression promoted proliferation ability. Xenograft tumor models revealed that the silencing of SBF2-AS1 inhibited tumor growth in vivo. We speculated that SBF2-AS1 might negatively regulate P21. RNA immunoprecipitation discovered that SBF2-AS2 could bind with a core component of polycomb repressive complex2, SUZ12. Additionally chromatin immunoprecipitation assay demonstrated that, after silencing SBF2-AS1, the enrichment of SUZ12 and trimethylation of histone 3 lysine 27 decreased at the promoter region of P21.We demonstrated that SBF2-AS1 is upregulated in NSCLC and promotes proliferation of NSCLC tumor cells. SBF2-AS1 may serve as a novel biomarker and potential therapeutic target for NSCLC patients.

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LEF1-AS1, long non-coding RNA, inhibits proliferation in myeloid malignancy.

Publications

LEF1-AS1, long non-coding RNA, inhibits proliferation in myeloid malignancy.

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