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.
Highlights
Multiple myeloma (MM) is a B-cell malignancy characterized by abnormal proliferation of plasma cells (PCs) within the bone marrow (BM)
We investigated and functionally characterized metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a nuclear-localized long non-coding RNAs (lncRNAs) highly expressed in MM [13]
We observed MALAT1 progressively upregulated in PCs from MGUS, SMM and overt MM patients as compared to normal PCs, suggesting a potential role in MM pathogenesis; we failed to demonstrate any significant association between MALAT1 expression and the clinical outcome in two available clinically annotated datasets tested
Summary
Multiple myeloma (MM) is a B-cell malignancy characterized by abnormal proliferation of plasma cells (PCs) within the bone marrow (BM). Functional genomics and epigenomics studies have demonstrated that, similar to proteincoding genes, short non-coding RNAs are dysregulated and play key roles in the pathogenesis of human cancers [2, 3], including MM [4]. Over half of the human genome is transcribed as long non-coding RNAs (lncRNAs), this term referring to non-coding transcripts longer than 200 nucleotides [5]. LncRNAs regulate gene transcription and mRNA translation by different mechanisms, including interaction with RNA-binding proteins, epigenetic modification of gene expression, or microRNA modulation [6]. It is not surprising that lncRNAs are implicated in relevant biological processes such as development, Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunit
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