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 Myo10 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.

中文翻译：

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MYO10 驱动癌症的基因组不稳定和炎症

基因组不稳定是人类癌症的一个标志；然而，潜在的机制仍然知之甚少。在这里，我们报告细胞质非常规肌球蛋白 X (MYO10) 调节基因组稳定性，通过它介导癌症中的炎症。MYO10 是一种不稳定的蛋白质，会经历泛素结合酶 H7 (UbcH7)/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，其表达水平易导致肿瘤进展和对免疫治疗的反应。过度表达 MYO10 会增加基因组不稳定性，提高环 GMP-AMP 合酶 (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，MYO10 的消耗改善了基因组的不稳定性并减少了炎症信号。Myo10显着抑制小鼠中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性促进肿瘤进展，这反过来又为免疫检查点阻断创造了免疫原性环境。