Targeting Druggabble Long Non-Coding RNA MALAT1: Epigenetic Regulation of CD38 and Energy Metabolism in Multiple Myeloma

Multiple myeloma (MM), the second most common hematologic malignancy, exhibits complex genetic and epigenetic abnormalities in its pathogenesis. Long non-coding RNA (lncRNA), defined as non-coding transcripts of more than 200 nucleotides, has been shown to play a crucial role in various critical cellular functions, including those related to malignant diseases. The lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), was found to be upregulated in both newly diagnosed and relapsed MM, indicating its potential oncogenic role. Previous studies also revealed therapeutic targeting MALAT exhibited a significant anti-MM effect. However, the specific mechanisms by which MALAT1 contributes to MM pathogenesis remain to be elucidated.

This study aims to investigate the role of this druggable lncRNA, MALAT1, in the development of MM. Initially, MALAT1 was overexpressed in MM cells, and its expression, along with CD38, was further upregulated in lenalidomide-resistant MM cell lines. Knocking down MALAT1 using antisense oligonucleotides (ASO) significantly decreased MM cell proliferation/viability in both lenalidomide-sensitive and resistant cells. RNAseq-based transcriptome profiles showed that genes related to the oxidative phosphorylation (OXPHOS) pathway were significantly down-regulated following MALAT1 knockdown. Downregulation of MALAT1 further reduced adenosine triphosphate (ATP) levels and elevated the generation of reactive oxygen species (ROS), suggesting those alterations in energy metabolism and the oxidative stress response in MM cells resulted in decreased cell viability. Furthermore, using a ChIP-PCR assay, MALAT1 epigenetically modulated CD38 expression via H3K27me3 modification, involving the polycomb repressive complex 2 (PRC2) complexes with H3K27 methyltransferase EZH2 and EED. Taken together, targeting the druggable lncRNA MALAT1 suppresses MM cell growth, reduces CD38 expression through epigenetic regulation by the PRC2 complexes, and has potential applications in treating lenalidomide resistance in MM.

No relevant conflicts of interest to declare.