Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity

Nicola Amodio, Maria Angelica Stamato, Giada Juli, Eugenio Morelli, Mariateresa Fulciniti, Martina Manzoni, Elisa Taiana, Luca Agnelli, Maria Eugenia Gallo Cantafio, Enrica Romeo, Lavinia Raimondi, Daniele Caracciolo, Valeria Zuccalà, Marco Rossi, Antonino Neri, Nikhil C. Munshi, Pierosandro Tagliaferri, Pierfrancesco Tassone

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Abstract

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still to be investigated. Here, we studied the functional significance and the druggability of the oncogenic lncRNA MALAT1 in MM. Targeting MALAT1 by novel LNA-gapmeR antisense oligonucleotide antagonized MM cell proliferation and triggered apoptosis both in vitro and in vivo in a murine xenograft model of human MM. Of note, antagonism of MALAT1 downmodulated the two major transcriptional activators of proteasome subunit genes, namely NRF1 and NRF2, and resulted in reduced trypsin, chymotrypsin and caspase-like proteasome activities and in accumulation of polyubiquitinated proteins. NRF1 and NRF2 decrease upon MALAT1 targeting was due to transcriptional activation of their negative regulator KEAP1, and resulted in reduced expression of anti-oxidant genes and increased ROS levels. In turn, NRF1 promoted MALAT1 expression thus establishing a positive feedback loop. Our findings demonstrate a crucial role of MALAT1 in the regulation of the proteasome machinery, and provide proof-of-concept that its targeting is a novel powerful option for the treatment of MM.

Original languageEnglish
Pages (from-to)1948-1957
Number of pages10
JournalLeukemia
Volume32
Issue number9
DOIs
Publication statusPublished - Sep 2018

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Long Noncoding RNA
Proteasome Endopeptidase Complex
Multiple Myeloma
Gene Expression
Antisense Oligonucleotides
Caspases
Heterografts
Oxidants
Transcriptional Activation
Genes
Cell Proliferation
Apoptosis
Proteins

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Amodio, N., Stamato, M. A., Juli, G., Morelli, E., Fulciniti, M., Manzoni, M., ... Tassone, P. (2018). Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity. Leukemia, 32(9), 1948-1957. https://doi.org/10.1038/s41375-018-0067-3

Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity. / Amodio, Nicola; Stamato, Maria Angelica; Juli, Giada; Morelli, Eugenio; Fulciniti, Mariateresa; Manzoni, Martina; Taiana, Elisa; Agnelli, Luca; Cantafio, Maria Eugenia Gallo; Romeo, Enrica; Raimondi, Lavinia; Caracciolo, Daniele; Zuccalà, Valeria; Rossi, Marco; Neri, Antonino; Munshi, Nikhil C.; Tagliaferri, Pierosandro; Tassone, Pierfrancesco.

In: Leukemia, Vol. 32, No. 9, 09.2018, p. 1948-1957.

Research output: Contribution to journalArticle

Amodio, N, Stamato, MA, Juli, G, Morelli, E, Fulciniti, M, Manzoni, M, Taiana, E, Agnelli, L, Cantafio, MEG, Romeo, E, Raimondi, L, Caracciolo, D, Zuccalà, V, Rossi, M, Neri, A, Munshi, NC, Tagliaferri, P & Tassone, P 2018, 'Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity', Leukemia, vol. 32, no. 9, pp. 1948-1957. https://doi.org/10.1038/s41375-018-0067-3
Amodio, Nicola ; Stamato, Maria Angelica ; Juli, Giada ; Morelli, Eugenio ; Fulciniti, Mariateresa ; Manzoni, Martina ; Taiana, Elisa ; Agnelli, Luca ; Cantafio, Maria Eugenia Gallo ; Romeo, Enrica ; Raimondi, Lavinia ; Caracciolo, Daniele ; Zuccalà, Valeria ; Rossi, Marco ; Neri, Antonino ; Munshi, Nikhil C. ; Tagliaferri, Pierosandro ; Tassone, Pierfrancesco. / Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity. In: Leukemia. 2018 ; Vol. 32, No. 9. pp. 1948-1957.
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