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.