ALKBH5-mediated m6A demethylation of lncRNA PVT1 plays an oncogenic role in osteosarcoma

Shuo Chen,Liwu Zhou,Yang Wang

doi:10.1186/s12935-020-1105-6

Abstract

BackgroundOsteosarcoma (OS) is one of the most common malignant bone tumors. Plasmacytoma variant translocation 1 (PVT1) is a well-known oncogenic long noncoding RNA (lncRNA). However, to date, the regulatory mechanism of PVT1 upregulation in OS remains unknown.MethodsqRT-PCR was carried out to test the expression level of PVT1 and ALKBH5. RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to detect the interaction of PVT1 with ALKBH5 and YTHDF2. Methylated RNA immune-precipitation (MeRIP) was used to examine the N6-methyladenosine (m6A) modification of PVT1 transcript.ResultsIn this study, we found that PVT1 expression was upregulated in OS tissues and cells and significantly related with clinical stage, tumor size, and prognosis of patients with OS. Further investigation revealed that N6-methyladenosine (m6A) demethylase ALKBH5 could associate with PVT1 and suppress its degradation. ALKBH5 decreased the m6A modification of PVT1, thus inhibiting the binding of reader protein YTHDF2 in PVT1. Functionally, ALKBH5-mediated PVT1 upregulation promoted the OS cell proliferation in vitro and tumor growth in vivo.ConclusionsOur study suggests that ALKBH5-mediated m6A modification of PVT1 contributes to OS tumorigenesis.

Highlights

Osteosarcoma (OS) is one of the most common malignant bone tumors
The results demonstrated a significant increase of Plasmacytoma variant translocation 1 (PVT1) expression in OS tissues compared to normal tissues (Fig. 1a)
We found that PVT1 expression was significantly correlated with clinical stage and tumor size (Table 1)

Summary

Introduction

Osteosarcoma (OS) is one of the most common malignant bone tumors. Osteosarcoma (OS) is one of the most common malignant bone tumors and mainly occurs in children and adolescents [1]. OS patients without distant metastasis usually had a relatively good prognosis [2]. The 5-year survival rate of OS patients with distant metastasis is only about 5–20% [3]. A better understanding of underlying mechanism promoting OS progression are urgently needed, which may be METTL14, and Wilms tumor 1-associated protein (WTAP) act as m 6A methyltransferases (“writers”). M 6A-binding proteins, including YTHDF1, YTHDF2, YTHDF3 and YTHDC1, have been identified to be the “readers” of m6A modification and regulate pre-mRNA processing, translation, and degradation [5].

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Results

Conclusion