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

Leukemia
Nicola AmodioPierfrancesco Tassone

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.

References

Oct 7, 1994·Cell·A Ciechanover
Dec 10, 1996·Proceedings of the National Academy of Sciences of the United States of America·R Venugopal, A K Jaiswal
Oct 5, 2010·Nature Reviews. Drug Discovery·Ramiro GarzonCarlo M Croce
Sep 20, 2011·Molecular Cell·Kevin C Wang, Howard Y Chang
Jan 21, 2012·Nature Reviews. Drug Discovery·Ryszard KoleSidney Altman
Feb 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Lucia KatoTasuku Honjo
Mar 27, 2013·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Tony GutschnerSven Diederichs
Nov 5, 2013·Biochimica Et Biophysica Acta·Per JohnssonKevin V Morris
Jul 22, 2014·Nature·Yinan ZhangBrendan D Manning
Nov 26, 2014·Nature Reviews. Clinical Oncology·Meletios A DimopoulosKenneth C Anderson
Feb 12, 2015·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Denise NiewerthJacqueline Cloos
Jun 18, 2015·Cancer Discovery·Francesca CottiniGiovanni Tonon
Jun 29, 2015·Free Radical Biology & Medicine·Takafumi Suzuki, Masayuki Yamamoto
Nov 4, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Annamaria GullàPierfrancesco Tassone
Feb 16, 2016·International Journal of Cancer. Journal International Du Cancer·Sonam Dhamija, Sven Diederichs
Mar 25, 2016·Nature·Eleonora LeucciJean-Christophe Marine
May 14, 2016·Oncotarget·Lucia NobiliAntonino Neri
May 20, 2016·Molecular Cancer Therapeutics·Nicola AmodioPierfrancesco Tassone
Sep 25, 2016·Methods in Molecular Biology·Benoit T RouxJames A Heward
Nov 29, 2016·Expert Opinion on Therapeutic Targets·Nicola AmodioDina Bellizzi
Dec 8, 2016·International Journal of Cancer. Journal International Du Cancer·Subash Chandra Gupta, Yashoda Nandan Tripathi
Feb 6, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kenneth C Anderson
Mar 2, 2017·The Journal of Clinical Investigation·Brian D AdamsFrank J Slack
Jul 21, 2017·Nature Reviews. Disease Primers·Shaji K KumarKenneth C Anderson

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Citations

Jan 19, 2019·Non-coding RNA·Irena Misiewicz-KrzeminskaNorma C Gutiérrez
Jan 27, 2019·Non-coding RNA·Romana ButovaRoman Hajek
Oct 30, 2018·Journal of Cellular Physiology·Qian YangShaoqing Ju
May 6, 2019·Non-coding RNA·Cinzia FedericoAldo M Roccaro
Feb 7, 2020·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Sajal Medha K AkkipeddiDawn M Carone
Feb 6, 2020·Cancers·Eugenio MorelliNicola Amodio
Mar 7, 2020·Journal of Cellular and Molecular Medicine·Ana Belén HerreroNorma C Gutiérrez
Apr 24, 2020·Journal of Cellular Physiology·Jingwen LiYu Hu
Jun 5, 2020·Antioxidants·Álvaro García-GuedeInmaculada Ibáñez-de-Caceres
Aug 28, 2020·Frontiers in Medicine·Guanhua LuXiao Zhu
Sep 8, 2018·Blood Cancer Journal·Hiroto OhguchiKenneth C Anderson
May 12, 2019·International Journal of Molecular Sciences·Beomku KangBonglee Kim
May 10, 2018·Journal of Hematology & Oncology·Nicola AmodioPierfrancesco Tassone
Oct 22, 2018·BMC Cardiovascular Disorders·Tarun PantZhi-Dong Ge
Nov 28, 2018·International Journal of Molecular Sciences·Yang-Hsiang LinKwang-Huei Lin
Sep 13, 2020·Non-coding RNA·Lavinia RaimondiNicola Amodio
Jun 17, 2020·Therapeutic Advances in Medical Oncology·Yidi QuDi Wang
Jun 22, 2020·Journal of Experimental & Clinical Cancer Research : CR·Katia GrillonePierfrancesco Tassone
Jun 7, 2020·Non-coding RNA·Gayatri ArunDavid L Spector
Jul 25, 2020·Haematologica·Annamaria Gulla, Kenneth C Anderson
Oct 21, 2020·Cancers·Cinzia CaprioAldo M Roccaro
Nov 12, 2020·International Journal of Molecular Sciences·Kang-Hoon LeeJe-Yoel Cho
Nov 12, 2020·Molecular Psychiatry·Sumin YangJae-Yeol Joo
Jan 7, 2021·Antioxidants & Redox Signaling·Emiliano Panieri, Luciano Saso
Jan 10, 2021·Seminars in Cancer Biology·Xiaorong LinErwei Song
Jan 12, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Bela GoyalSubash Chandra Gupta
Jun 26, 2020·Seminars in Cell & Developmental Biology·Tim Vierbuchen, Katherine A Fitzgerald

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Methods Mentioned

BETA
antisense oligonucleotide
Assay
immunoprecipitation
xenograft
xenografts
transfection
RIP
ChIP

Software Mentioned

GraphPad
GSEA
Calcusyn

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