Mechanotransduction sensing of tissue architecture and cellular microenvironment is a fundamental regulator of cell fate, including cancer. Meanwhile, long noncoding RNAs (lncRNAs) play multifunctions during cancer development and treatment. However, the link between lncRNAs and cellular mechanotransduction in the context of cancer progression has not yet been elucidated. In this study, using atomic force microscopy (AFM), we find that ionizing radiation reduces tumor stiffness. Ionizing radiation-induced lncRNA CRYBG3 can blunt YAP/TAZ activity through interference with mechanotransduction, resulting in the inhibition of cell proliferation, invasion, and metastasis of lung cancer cells. In vivo, we found that loss of lncRNA CRYBG3 could power the tumor initiation and metastasis ability, but this was abolished by concomitant deplete TAZ. At the molecular level, lncRNA CRYBG3 that in turn dysregulates F-actin organization, activates the LATS1/2 kinase, all in all resulting in YAP/TAZ nuclear exclusion. Our research proposes that lncRNA CRYBG3 is a mediator of radiotherapy through its control of cancer-tissue mechanotransduction and wiring YAP/TAZ activity to control tumor growth and metastasis.

组织结构和细胞微环境的机械转导传感是细胞命运的基本调节器，包括癌症。同时，长链非编码 RNA (lncRNA) 在癌症发展和治疗过程中发挥着多重作用。然而，在癌症进展的背景下，lncRNA 与细胞机械转导之间的联系尚未阐明。在这项研究中，使用原子力显微镜 (AFM)，我们发现电离辐射降低了肿瘤硬度。电离辐射诱导的 lncRNA CRYBG3 可通过干扰机械转导减弱 YAP/TAZ 活性，从而抑制肺癌细胞的增殖、侵袭和转移。在体内，我们发现 lncRNA CRYBG3 的缺失可以促进肿瘤的发生和转移能力，但这被伴随的 TAZ 耗尽而取消。在分子水平上，lncRNA CRYBG3 反过来失调 F-肌动蛋白组织，激活 LATS1/2 激酶，所有这些都导致 YAP/TAZ 核排斥。我们的研究表明，lncRNA CRYBG3 通过控制癌组织机械转导和连接 YAP/TAZ 活性来控制肿瘤生长和转移，从而成为放射治疗的介质。