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

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.

FAM46C controls antibody production by the polyadenylation of immunoglobulin mRNAs and inhibits cell migration in multiple myeloma

“…We found that some of the few genes deregulated in the FAM46C KO clones, such as MAGED1, RHOBTB1 and MALAT1 , had previously been associated with cell migration MALAT1 was found to be up‐regulated by FAM46C inactivation in the three HMCLs used in this study. This lncRNA was overexpressed in a wide variety of solid tumours and also in haematological malignancies, including MM . Moreover, high levels of expression of MALAT1 in MM have been associated with the onset of the disease, progression from normal PCs to MM and extramedullary dissemination .…”

The Non-Coding RNA Landscape of Plasma Cell Dyscrasias

“…Mechanistically, we established that MALAT1 interacts with EZH2 to regulate KEAP1 expression, triggering a KEAP1-dependent induction of NRF1/2, two relevant transcriptional activators of proteasome subunit genes [152]. As a corollary of our work, we provided evidence of MALAT1 druggability using LNA gapmeRs in vitro and in vivo in NOD-SCID mice bearing MM xenografts [152]. Hu et al reported that MALAT1 acts as a scaffold in the formation of PARP1/LIG3 complexes that recognize DSBs on DNA and activate the alternative non-homologous end joining (A-NHEJ) DNA repair in MM cells [151].…”

“…To date, only a few lncRNAs have been functionally investigated in MM-including MALAT1 [151][152][153], NEAT1 [154,155], CCAT1 [156] and H19 [157,158]. Importantly, different reports converge in defining the oncogenic role of MALAT1 in MM, which was found upregulated during the progression from intra-medullary to extra-medullary disease, with the higher levels associated with shorter OS and PFS [153].…”

“…Importantly, different reports converge in defining the oncogenic role of MALAT1 in MM, which was found upregulated during the progression from intra-medullary to extra-medullary disease, with the higher levels associated with shorter OS and PFS [153]. We explored its functional role in MM and demonstrated that it may promote cell survival by regulating the expression and activity of the proteasome machinery [152]. Mechanistically, we established that MALAT1 interacts with EZH2 to regulate KEAP1 expression, triggering a KEAP1-dependent induction of NRF1/2, two relevant transcriptional activators of proteasome subunit genes [152].…”

“…We explored its functional role in MM and demonstrated that it may promote cell survival by regulating the expression and activity of the proteasome machinery [152]. Mechanistically, we established that MALAT1 interacts with EZH2 to regulate KEAP1 expression, triggering a KEAP1-dependent induction of NRF1/2, two relevant transcriptional activators of proteasome subunit genes [152]. As a corollary of our work, we provided evidence of MALAT1 druggability using LNA gapmeRs in vitro and in vivo in NOD-SCID mice bearing MM xenografts [152].…”