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Epigenetic regulation of HOTAIR in advanced chronic myeloid leukemia

Authors Li Z, Luo J

Received 28 February 2018

Accepted for publication 16 April 2018

Published 5 November 2018 Volume 2018:10 Pages 5349—5362

DOI https://doi.org/10.2147/CMAR.S166859

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Jaya Mallela

Peer reviewer comments 2

Editor who approved publication: Dr Kenan Onel


Ziye Li, Jianmin Luo

Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People’s Republic of China

Purpose: Chronic myeloid leukemia (CML) accounts for ~10% of leukemia cases, and its progression involves epigenetic gene regulation. This study investigated epigenetic regulation of HOTAIR and its target microRNA, miR-143, in advanced CML.
Patients and methods: We first isolated bone marrow mononuclear cells from 70 patients with different phases of CML and from healthy donors as normal control; we also cultured K562 and KCL22 cells, treated with demethylation drug; MTT assay, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), methylation-specific polymerase chain reaction (MSP), Western blot, luciferase assay, RNA pull-down assay and RNA-binding protein immunoprecipitation (RIP) assay were performed.
Result: As measured by qPCR, HOTAIR expression in K562 cells, KCL22 cells, and samples from cases of advanced-stage CML increased with levels of several DNA methyltransferases and histone deacetylates, including DNMT1, DNMT3A, HDAC1, EZH2, and LSD1, and miR-143 levels were decreased and HOTAIR levels were increased. Treatment with 5-azacytidine, a DNA methylation inhibitor, decreased DNMT1, DNMT3A, HDAC1, EZH2, LSD1 mRNA, protein levels, and HOTAIR mRNA levels but increased miR-143 levels. HOTAIR knockdown and miR-143 overexpression both inhibited proliferation and promoted apoptosis in KCL22 and K562 cells through the PI3K/AKT pathway. RNA pull-down, mass spectrometry, and RIP assays showed that HOTAIR interacted with EZH2 and LSD1. A dual-luciferase assay demonstrated that HOTAIR interacted with miR-143.
Conclusion: Our findings demonstrate the key epigenetic interactions of HOTAIR related to CML progression and suggest HOTAIR as a potential therapeutic target for advanced CML. Furthermore, our results support the use of demethylation drugs as a CML treatment strategy.

Keywords: lncRNA HOTAIR, miR-143, epigenetic, PI3K/AKT, EZH2
 

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