Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma

Abstract

Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) is a highly conserved long non-coding RNA (lncRNA). Overexpression of MALAT1 has been demonstrated to related to poor prognosis of multiple myeloma(MM) patients. Here, we demonstrated that MALAT1 plays important roles in MM DNA repair and cell death. We found bone marrow plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM express elevated MALAT1 and involve in alternative-non-homozygous end joining (A-NHEJ) pathway by binding to PARP1 and LIG3, two key components of the A-NHEJ protein complex. Degradation of the MALAT1 RNA by RNase H using antisense gapmer DNA oligos in MM cells stimulated poly-ADP-ribosylation of nuclear proteins, defected the DNA repair pathway, and further provoked apoptotic pathways. Anti-MALAT1 therapy combined with PARP1 inhibitor or proteasome inhibitor in MM cells showed a synergistic effect in vitro. Furthermore, using novel single wall carbon nanotube (SWCNT) conjugated with anti-MALAT1 oligos, we successfully knocked down MALAT1 RNA in cultured MM cell lines and xenograft murine models. Most importantly, anti-MALAT1 therapy induced DNA damage and cell apoptosis in vivo, indicating that MALAT1 could serve as a potential novel therapeutic target for MM treatment.

The Non-Coding RNA Landscape of Plasma Cell Dyscrasias

“…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]. Moreover, MALAT1 inhibition by ASOs was proven to synergize both with PARP and proteasome inhibitors, and a nanoparticle-based approach significantly increased the in vivo delivery of MALAT1 inhibitors [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].…”

“…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]. Moreover, MALAT1 inhibition by ASOs was proven to synergize both with PARP and proteasome inhibitors, and a nanoparticle-based approach significantly increased the in vivo delivery of MALAT1 inhibitors [151]. NEAT1 is another lncRNA that has been deeply investigated in MM.…”

Investigation of the Genome-Wide Genetic and Epigenetic Networks for Drug Discovery Based on Systems Biology Approaches in Colorectal Cancer

“…DNA damage and repair are double-edged swords in cancer. DNA damage, coupled with error-prone repair, could drive cancer progression by promoting genomic or genetic instability (Doksani and De Lange, 2016;Hu et al, 2018). Based on our data analysis result, we infer that the DNA repair in response to DNA damage provides a possibility to prevent CRC cells from progressing.…”

“…The first pathway starts with receptor GRID2, which also appears in mid-stage CRC cells, and transmits the signal to TF WDR4 to upregulate target gene LIG3. LIG3 has been investigated in studies concerning DNA repair (Murray et al, 2011;Hu et al, 2018). DNA damage and repair are double-edged swords in cancer.…”