Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
Leukemia. 2018 Oct;32(10):2250-2262. doi: 10.1038/s41375-018-0104-2. Epub 2018 Mar 22.
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.
转移相关肺腺癌转录本 1（MALAT1）是一种高度保守的长非编码 RNA（lncRNA）。已有研究表明，MALAT1 的过表达与多发性骨髓瘤（MM）患者的预后不良有关。在这里，我们证明 MALAT1 在 MM 的 DNA 修复和细胞死亡中发挥重要作用。我们发现，来自意义未明的单克隆丙种球蛋白病（MGUS）和 MM 患者的骨髓浆细胞表达升高的 MALAT1，并通过与 PARP1 和 LIG3 结合，参与非同源末端连接（NHEJ）途径，PARP1 和 LIG3 是 A-NHEJ 蛋白复合物的两个关键组成部分。在 MM 细胞中，使用反义 gapmer DNA 寡核苷酸通过 RNase H 降解 MALAT1 RNA 可刺激核蛋白的聚 ADP-核糖基化，使 DNA 修复途径缺陷，并进一步引发凋亡途径。在 MM 细胞中，MALAT1 治疗联合 PARP1 抑制剂或蛋白酶体抑制剂在体外显示出协同作用。此外，我们使用新型单壁碳纳米管（SWCNT）与抗 MALAT1 寡核苷酸偶联，成功地敲低了培养的 MM 细胞系和异种移植鼠模型中的 MALAT1 RNA。最重要的是，MALAT1 治疗在体内诱导了 DNA 损伤和细胞凋亡，表明 MALAT1 可作为 MM 治疗的潜在新的治疗靶点。
