Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p

Pengfei Wu,Qun Chen,Xiangqi Meng,Lin Lin,Chuanlu Jiang,Ruijia Wang,Ziwei Li,Chunbin Duan,Jinquan Cai,Yansheng Li,Bo Han,Chunsheng Kang

doi:10.1038/s41467-019-10025-2

Abstract

Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.

Highlights

Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 300052 Tianjin, China. 3These authors contributed : Pengfei Wu, Qun Chen. 4These authors jointly supervised: Jinquan Cai, Chunsheng Kang, Chuanlu Jiang
Single-sample gene set enrichment analysis illustrated that the top 30 upregulated Long noncoding RNAs (lncRNAs) were associated with the Gene Ontology (GO) and KEGG pathways enriched in the regulation of DNA repair and the MAPK signaling pathway, among others (Fig. 1d)
The top 10 upregulated lncRNAs between LN229 and 229R cells are listed in the volcano plot (Fig. 1e), and were subjected to validation by quantitative real time polymerase chain reaction using four groups of parental and resistant GBM cells (Supplementary Fig. 2a)

Summary

Introduction

Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, 300052 Tianjin, China. 3These authors contributed : Pengfei Wu, Qun Chen. 4These authors jointly supervised: Jinquan Cai, Chunsheng Kang, Chuanlu Jiang. A G>A change at rs1111655237 in exon 4 of LINC00673 creates a target site for miR-1231 binding, decreases PTPN11 ubiquitination, attenuates the effect of LINC00673 in an allele-specific manner, conferring susceptibility to tumorigenesis[7], and indicating the importance of embedded miRNAs in lncRNAs regulating oncogenic signaling pathways. Glioblastoma (GBM) is the most common malignant primary brain cancer in adults, with a median survival of 14.6 months upon diagnosis[10,11], and a 5-year survival rate of only 5.5%12. This poor prognosis is due to therapeutic resistance and tumor recurrence following surgical removal, and the treatment of such brain tumors remains a challenge[13]. It is urgent to elucidate the underlying lncRNA-based mechanisms of TMZ resistance in GBM patients

Methods

Results

Conclusion