Mayca Pozo Franklin, Geng Xinran, Tamagno Ilaria, Jackson Mark W, Heimsath Ernest G, Hammer John A, Cheney Richard E, Zhang Youwei
Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Department of Pathology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Sci Adv. 2021 Sep 17;7(38):eabg6908. doi: 10.1126/sciadv.abg6908. Epub 2021 Sep 15.
Genomic instability is a hallmark of human cancer; yet the underlying mechanisms remain poorly understood. Here, we report that the cytoplasmic unconventional Myosin X (MYO10) regulates genome stability, through which it mediates inflammation in cancer. MYO10 is an unstable protein that undergoes ubiquitin-conjugating enzyme H7 (UbcH7)/β-transducin repeat containing protein 1 (β-TrCP1)–dependent degradation. MYO10 is upregulated in both human and mouse tumors and its expression level predisposes tumor progression and response to immune therapy. Overexpressing MYO10 increased genomic instability, elevated the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)–dependent inflammatory response, and accelerated tumor growth in mice. Conversely, depletion of MYO10 ameliorated genomic instability and reduced the inflammation signaling. Further, inhibiting inflammation or disrupting significantly suppressed the growth of both human and mouse breast tumors in mice. Our data suggest that MYO10 promotes tumor progression through inducing genomic instability, which, in turn, creates an immunogenic environment for immune checkpoint blockades.
基因组不稳定是人类癌症的一个标志；然而其潜在机制仍知之甚少。在此，我们报告细胞质非常规肌球蛋白X（MYO10）通过调节基因组稳定性介导癌症炎症。MYO10是一种不稳定蛋白，通过泛素结合酶H7（UbcH7）/含β-转导蛋白重复序列蛋白1（β-TrCP1）依赖性降解。MYO10在人类和小鼠肿瘤中均上调，其表达水平影响肿瘤进展及对免疫治疗的反应。过表达MYO10会增加基因组不稳定，增强环磷酸鸟苷-腺苷酸合成酶（cGAS）/干扰素基因刺激物（STING）依赖性炎症反应，并加速小鼠肿瘤生长。相反，敲除MYO10可改善基因组不稳定并减少炎症信号传导。此外，抑制炎症或破坏（此处原文不完整）显著抑制了小鼠体内人类和小鼠乳腺肿瘤的生长。我们的数据表明，MYO10通过诱导基因组不稳定促进肿瘤进展，进而为免疫检查点阻断创造免疫原性环境。
