Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.
The Eric J. Poulin Centre for Neuromuscular Diseases, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Cell Oncol (Dordr). 2021 Aug;44(4):851-870. doi: 10.1007/s13402-021-00607-y. Epub 2021 Apr 26.
Recent work has highlighted the therapeutic potential of targeting autophagy to modulate cell survival in a variety of diseases including cancer. Recently, we found that the RNA-binding protein Staufen1 (STAU1) is highly expressed in alveolar rhabdomyosarcoma (ARMS) and that this abnormal expression promotes tumorigenesis. Here, we asked whether STAU1 is involved in the regulation of autophagy in ARMS cells.
We assessed the impact of STAU1 expression modulation in ARMS cell lines (RH30 and RH41), non-transformed skeletal muscle cells (C2C12) and STAU1-transgenic mice using complementary techniques.
We found that STAU1 silencing reduces autophagy in the ARMS cell lines RH30 and RH41, while increasing their apoptosis. Mechanistically, this inhibitory effect was found to be caused by a direct negative impact of STAU1 depletion on the stability of Beclin-1 (BECN1) and ATG16L1 mRNAs, as well as by an indirect inhibition of JNK signaling via increased expression of Dual specificity phosphatase 8 (DUSP8). Pharmacological activation of JNK or expression silencing of DUSP8 was sufficient to restore autophagy in STAU1-depleted cells. By contrast, we found that STAU1 downregulation in non-transformed skeletal muscle cells activates autophagy in a mTOR-dependent manner, without promoting apoptosis. A similar effect was observed in skeletal muscles obtained from STAU1-overexpressing transgenic mice.
Together, our data indicate an effect of STAU1 on autophagy regulation in ARMS cells and its differential role in non-transformed skeletal muscle cells. Our findings suggest a cancer-specific potential of targeting STAU1 for the treatment of ARMS.
最近的研究强调了靶向自噬来调节包括癌症在内的多种疾病中的细胞存活的治疗潜力。最近，我们发现 RNA 结合蛋白 Staufen1（STAU1）在肺泡横纹肌肉瘤（ARMS）中高度表达，这种异常表达促进了肿瘤的发生。在这里，我们想知道 STAU1 是否参与了 ARMS 细胞中自噬的调节。
我们使用互补技术评估了 STAU1 表达调节在 ARMS 细胞系（RH30 和 RH41）、非转化骨骼肌细胞（C2C12）和 STAU1 转基因小鼠中的影响。
我们发现 STAU1 沉默减少了 ARMS 细胞系 RH30 和 RH41 中的自噬，同时增加了它们的凋亡。从机制上讲，这种抑制作用是由于 STAU1 耗竭直接负向影响 Beclin-1（BECN1）和 ATG16L1 mRNA 的稳定性，以及通过 Dual specificity phosphatase 8（DUSP8）表达的增加间接抑制 JNK 信号。JNK 的药理学激活或 DUSP8 的表达沉默足以恢复 STAU1 耗竭细胞中的自噬。相比之下，我们发现 STAU1 在非转化骨骼肌细胞中的下调以 mTOR 依赖的方式激活自噬，而不会促进凋亡。在 STAU1 过表达转基因小鼠的骨骼肌中也观察到类似的效果。
总的来说，我们的数据表明 STAU1 对 ARMS 细胞中自噬的调节有影响，并且在非转化骨骼肌细胞中有不同的作用。我们的发现表明，针对 STAU1 的治疗可能具有治疗 ARMS 的癌症特异性潜力。
