DNA损伤
癌症研究
细胞凋亡
PARP1
DNA修复
生物
程序性细胞死亡
聚ADP核糖聚合酶
马拉特1
分子生物学
DNA
核糖核酸
长非编码RNA
生物化学
基因
聚合酶
作者
Yi Hu,Jianhong Lin,Fang Hua,Jing Fang,Chen Li,Wei Chen,Shuang Liu,Sarah L. Ondrejka,Zihua Gong,Frederic J. Reu,Jaroslaw P. Maciejewski,Qing Yi,Jianjun Zhao
出处
期刊:Leukemia
[Springer Nature]
日期:2018-03-22
卷期号:32 (10): 2250-2262
被引量:132
标识
DOI:10.1038/s41375-018-0104-2
摘要
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.
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