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

• Published in: Leukemia Vol. 32; no. 9; pp. 1948 - 1957
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: 13/2; 13/95; 42/109; 45/77; 45/90; 631/67/1990/804; 631/80/86; 692/699/67/1990/804; Antagonism; Antisense oligonucleotides; Apoptosis; Biological activity; Cancer genetics; Cancer Research; Caspase; Cell proliferation; Chymotrypsin; Critical Care Medicine; Development and progression; Drug therapy; Feedback loops; Gene expression; Genes; Genetic aspects; Health aspects; Hematology; Innovations; Intensive; Internal Medicine; Medicine; Medicine & Public Health; Molecular targeted therapy; Multiple myeloma; Oncology; Positive feedback; Proteasomes; Proteins; Reactive oxygen species; Transcription (Genetics); Transcription activation; Transcription factors; Trypsin; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-018-0067-3

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.