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

Nat Commun. 2019 May 3;10(1):2045. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / metabolism
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Profiling / methods
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics
  • Glioblastoma / mortality
  • Glioblastoma / pathology
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / metabolism*
  • Middle Aged
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism*
  • Oligonucleotide Array Sequence Analysis / methods
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • RNA, Long Noncoding / metabolism*
  • Survival Analysis
  • Temozolomide / pharmacology*
  • Temozolomide / therapeutic use
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Alkylating
  • MIRN20a microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • Tumor Suppressor Proteins
  • DNA Modification Methylases
  • MGMT protein, human
  • O(6)-Methylguanine-DNA Methyltransferase
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • DNA Repair Enzymes
  • Temozolomide