Long non-coding RNA NEAT1 targeting impairs the DNA repair machinery and triggers anti-tumor activity in multiple myeloma

Elisa Taiana, Vanessa Favasuli, Domenica Ronchetti, Katia Todoerti, Francesca Pelizzoni, Martina Manzoni, Marzia Barbieri, Sonia Fabris, Ilaria Silvestris, Maria Eugenia Gallo Cantafio, Natalia Platonova, Valeria Zuccalà, Lorenza Maltese, Debora Soncini, Samantha Ruberti, Michele Cea, Raffaella Chiaramonte, Nicola Amodio, Pierfrancesco Tassone, Luca AgnelliAntonino Neri

Research output: Contribution to journalArticle

Abstract

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still open questions. Herein, we investigated the functional significance of the oncogenic lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in MM. Our study demonstrates that NEAT1 expression level is higher in MM than in the majority of hematological malignancies. NEAT1 silencing by novel LNA-gapmeR antisense oligonucleotide inhibits MM cell proliferation and triggers apoptosis in vitro and in vivo murine MM model as well. By transcriptome analyses, we found that NEAT1 targeting downregulates genes involved in DNA repair processes including the Homologous Recombination pathway, which in turn results in massive DNA damage. These findings may explain the synergistic impact on apoptosis observed in MM cell lines co-treated with inhibitors of both NEAT1 and PARP. The translational significance of NEAT1 targeting is further underlined by its synergistic effects with the most common drugs administered for MM treatment, including bortezomib, carfilzomib, and melphalan. Overall, NEAT1 silencing is associated with a chemo-sensitizing effect of both conventional and novel therapies, and its targeting could therefore represent a promising strategy for novel anti-MM therapeutic options.

Original languageEnglish
Pages (from-to)234-244
JournalLeukemia
Volume34
Issue number1
DOIs
Publication statusPublished - 2020

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Long Noncoding RNA
Multiple Myeloma
DNA Repair
Neoplasms
Apoptosis
Melphalan
Gene Targeting
Antisense Oligonucleotides
Homologous Recombination
Gene Expression Profiling
Hematologic Neoplasms
DNA Damage
Therapeutics
Down-Regulation
Cell Proliferation
Cell Line

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Long non-coding RNA NEAT1 targeting impairs the DNA repair machinery and triggers anti-tumor activity in multiple myeloma. / Taiana, Elisa; Favasuli, Vanessa; Ronchetti, Domenica; Todoerti, Katia; Pelizzoni, Francesca; Manzoni, Martina; Barbieri, Marzia; Fabris, Sonia; Silvestris, Ilaria; Gallo Cantafio, Maria Eugenia; Platonova, Natalia; Zuccalà, Valeria; Maltese, Lorenza; Soncini, Debora; Ruberti, Samantha; Cea, Michele; Chiaramonte, Raffaella; Amodio, Nicola; Tassone, Pierfrancesco; Agnelli, Luca; Neri, Antonino.

In: Leukemia, Vol. 34, No. 1, 2020, p. 234-244.

Research output: Contribution to journalArticle

Taiana, E, Favasuli, V, Ronchetti, D, Todoerti, K, Pelizzoni, F, Manzoni, M, Barbieri, M, Fabris, S, Silvestris, I, Gallo Cantafio, ME, Platonova, N, Zuccalà, V, Maltese, L, Soncini, D, Ruberti, S, Cea, M, Chiaramonte, R, Amodio, N, Tassone, P, Agnelli, L & Neri, A 2020, 'Long non-coding RNA NEAT1 targeting impairs the DNA repair machinery and triggers anti-tumor activity in multiple myeloma', Leukemia, vol. 34, no. 1, pp. 234-244. https://doi.org/10.1038/s41375-019-0542-5
Taiana, Elisa ; Favasuli, Vanessa ; Ronchetti, Domenica ; Todoerti, Katia ; Pelizzoni, Francesca ; Manzoni, Martina ; Barbieri, Marzia ; Fabris, Sonia ; Silvestris, Ilaria ; Gallo Cantafio, Maria Eugenia ; Platonova, Natalia ; Zuccalà, Valeria ; Maltese, Lorenza ; Soncini, Debora ; Ruberti, Samantha ; Cea, Michele ; Chiaramonte, Raffaella ; Amodio, Nicola ; Tassone, Pierfrancesco ; Agnelli, Luca ; Neri, Antonino. / Long non-coding RNA NEAT1 targeting impairs the DNA repair machinery and triggers anti-tumor activity in multiple myeloma. In: Leukemia. 2020 ; Vol. 34, No. 1. pp. 234-244.
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abstract = "The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still open questions. Herein, we investigated the functional significance of the oncogenic lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in MM. Our study demonstrates that NEAT1 expression level is higher in MM than in the majority of hematological malignancies. NEAT1 silencing by novel LNA-gapmeR antisense oligonucleotide inhibits MM cell proliferation and triggers apoptosis in vitro and in vivo murine MM model as well. By transcriptome analyses, we found that NEAT1 targeting downregulates genes involved in DNA repair processes including the Homologous Recombination pathway, which in turn results in massive DNA damage. These findings may explain the synergistic impact on apoptosis observed in MM cell lines co-treated with inhibitors of both NEAT1 and PARP. The translational significance of NEAT1 targeting is further underlined by its synergistic effects with the most common drugs administered for MM treatment, including bortezomib, carfilzomib, and melphalan. Overall, NEAT1 silencing is associated with a chemo-sensitizing effect of both conventional and novel therapies, and its targeting could therefore represent a promising strategy for novel anti-MM therapeutic options.",
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AU - Zuccalà, Valeria

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AU - Cea, Michele

AU - Chiaramonte, Raffaella

AU - Amodio, Nicola

AU - Tassone, Pierfrancesco

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AU - Neri, Antonino

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