Dannheisig David P, Schimansky Anna, Donow Cornelia, Pfister Astrid S
Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany.
Cancers (Basel). 2021 Dec 10;13(24):6220. doi: 10.3390/cancers13246220.
Ribosome biogenesis is essential for protein synthesis, cell growth and survival. The process takes places in nucleoli and is orchestrated by various proteins, among them RNA polymerases I-III as well as ribosome biogenesis factors. Perturbation of ribosome biogenesis activates the nucleolar stress response, which classically triggers cell cycle arrest and apoptosis. Nucleolar stress is utilized in modern anti-cancer therapies, however, also contributes to the development of various pathologies, including cancer. Growing evidence suggests that nucleolar stress stimulates compensatory cascades, for instance bulk autophagy. However, underlying mechanisms are poorly understood. Here we demonstrate that induction of nucleolar stress activates expression of key autophagic regulators such as and , essential for generation of autophagosomes. We show that knockdown of the ribosomopathy factor SBDS, or of key ribosome biogenesis factors (PPAN, NPM, PES1) is associated with enhanced levels of ATG7 in cancer cells. The same holds true when interfering with RNA polymerase I function by either pharmacological inhibition (CX-5461) or depletion of the transcription factor UBF-1. Moreover, we demonstrate that RNA pol I inhibition by CX-5461 stimulates autophagic flux. Together, our data establish that nucleolar stress affects transcriptional regulation of autophagy. Given the contribution of both axes in propagation or cure of cancer, our data uncover a connection that might be targeted in future.
核糖体生物合成对于蛋白质合成、细胞生长和存活至关重要。该过程在核仁中进行，由多种蛋白质协调，其中包括RNA聚合酶I - III以及核糖体生物合成因子。核糖体生物合成的扰动会激活核仁应激反应，经典地触发细胞周期停滞和凋亡。核仁应激在现代抗癌疗法中被利用，但也促成了包括癌症在内的各种病理的发展。越来越多的证据表明，核仁应激会刺激代偿性级联反应，例如大量自噬。然而，其潜在机制尚不清楚。在这里，我们证明核仁应激的诱导会激活关键自噬调节因子如 和 的表达，这些因子对于自噬体的产生至关重要。我们表明，核糖体病因子SBDS或关键核糖体生物合成因子（PPAN、NPM、PES1）的敲低与癌细胞中ATG7水平的升高有关。当通过药理学抑制（CX - 5461）或转录因子UBF - 1的缺失来干扰RNA聚合酶I的功能时，情况也是如此。此外，我们证明CX - 5461对RNA pol I的抑制会刺激自噬流。总之，我们的数据表明核仁应激会影响自噬的转录调控。鉴于这两个轴在癌症传播或治愈中的作用，我们的数据揭示了一个未来可能会被靶向的联系。
