Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Leukemia. 2018 Sep;32(9):1948-1957. doi: 10.1038/s41375-018-0067-3. Epub 2018 Feb 22.
The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) are still to be investigated. Here, we studied the functional significance and the druggability of the oncogenic lncRNA MALAT1 in MM. Targeting MALAT1 by novel LNA-gapmeR antisense oligonucleotide antagonized MM cell proliferation and triggered apoptosis both in vitro and in vivo in a murine xenograft model of human MM. Of note, antagonism of MALAT1 downmodulated the two major transcriptional activators of proteasome subunit genes, namely NRF1 and NRF2, and resulted in reduced trypsin, chymotrypsin and caspase-like proteasome activities and in accumulation of polyubiquitinated proteins. NRF1 and NRF2 decrease upon MALAT1 targeting was due to transcriptional activation of their negative regulator KEAP1, and resulted in reduced expression of anti-oxidant genes and increased ROS levels. In turn, NRF1 promoted MALAT1 expression thus establishing a positive feedback loop. Our findings demonstrate a crucial role of MALAT1 in the regulation of the proteasome machinery, and provide proof-of-concept that its targeting is a novel powerful option for the treatment of MM.
长链非编码 RNA（lncRNA）在多发性骨髓瘤（MM）中的生物学作用和治疗潜力仍有待研究。在这里，我们研究了致癌 lncRNA MALAT1 在 MM 中的功能意义和可药性。新型 LNA-gapmeR 反义寡核苷酸靶向 MALAT1，在体外和体内人 MM 异种移植模型中均拮抗 MM 细胞增殖并触发细胞凋亡。值得注意的是，MALAT1 的拮抗作用下调了蛋白酶体亚基基因的两个主要转录激活因子，即 NRF1 和 NRF2，并导致蛋白酶体的胰蛋白酶、糜蛋白酶和半胱天冬酶样活性降低，以及多聚泛素化蛋白的积累。MALAT1 靶向后 NRF1 和 NRF2 的减少是由于其负调节因子 KEAP1 的转录激活，导致抗氧化基因表达减少和 ROS 水平增加。反过来，NRF1 促进 MALAT1 的表达，从而建立了一个正反馈回路。我们的研究结果表明 MALAT1 在蛋白酶体机制的调节中起着关键作用，并为其靶向治疗 MM 提供了概念验证。
