Baruch Esther, Nizri-Megnaji Tali, Berkowitz Oron, Ginsberg Doron
The Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel.
Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Oncotarget. 2021 May 25;12(11):1072-1082. doi: 10.18632/oncotarget.27962.
The transcription factor E2F1 induces both proliferation and apoptosis and is a critical downstream target of the tumor suppressor RB. Long non-coding RNAs (lncRNAs) are major regulators of many cellular processes, including cell cycle progression and cell proliferation. However, the mode of action as well as the transcriptional regulation of most lncRNAs are only beginning to be understood. Here, we report that a novel human lncRNA, LAPAS1, is an E2F1- regulated lncRNA that affects S phase progression. Inhibition of LAPAS1 expression increases percentage of S phase cells, and its silencing in synchronized cells delays their progression through S phase. In agreement with its suggested role in cell cycle progression, prolonged inhibition of LAPAS1 attenuates proliferation of human cancer cells. Our data demonstrate that LAPAS1 predominantly functions in trans to repress expression of Sphingolipid Transporter 2 (SPNS2). Importantly, knockdown of SPNS2 rescues the effect of LAPAS1 silencing on cell cycle and cell proliferation. Notably, low levels of LAPAS1 are associated with increased survival of kidney cancer patients. Summarily, we identify LAPAS1 as a novel E2F-regulated lncRNA that has a potential role in human cancer and regulates cell-cycle progression and cell proliferation, at least in part, via regulation of SPNS2.
转录因子E2F1既能诱导细胞增殖又能诱导细胞凋亡，是肿瘤抑制因子RB的关键下游靶点。长链非编码RNA（lncRNA）是许多细胞过程的主要调节因子，包括细胞周期进程和细胞增殖。然而，大多数lncRNA的作用模式以及转录调控才刚刚开始被了解。在此，我们报道一种新型人类lncRNA，LAPAS1，是一种受E2F1调控的lncRNA，它影响S期进程。抑制LAPAS1表达会增加S期细胞的百分比，在同步化细胞中使其沉默会延迟它们通过S期的进程。与其在细胞周期进程中的作用一致，长期抑制LAPAS1会减弱人类癌细胞的增殖。我们的数据表明，LAPAS1主要通过反式作用抑制鞘脂转运蛋白2（SPNS2）的表达。重要的是，敲低SPNS2可挽救LAPAS1沉默对细胞周期和细胞增殖的影响。值得注意的是，LAPAS1低水平与肾癌患者生存率增加相关。总之，我们鉴定出LAPAS1是一种新型的受E2F调控的lncRNA，它在人类癌症中具有潜在作用，并且至少部分通过调节SPNS2来调控细胞周期进程和细胞增殖。
