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Leukemia. 2018 Sep;32(9):1948-1957. doi: 10.1038/s41375-018-0067-3. Epub 2018 Feb 22.

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

Author information

1
Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.
2
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
4
Hematology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
5
Laboratory of Tissue Engineering, Rizzoli Orthopedic Institute, Palermo, Italy.
6
Pathology Unit, Pugliese-Ciaccio Hospital, Catanzaro, Italy.
7
VA Boston Healthcare System, West Roxbury, Boston, MA, USA.
8
Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy. tassone@unicz.it.
9
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA. tassone@unicz.it.

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.

PMID:
29487387
PMCID:
PMC6127082
DOI:
10.1038/s41375-018-0067-3
[Indexed for MEDLINE]
Free PMC Article

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