The USP22 deubiquitinase, a component of the SAGA histone modifying complex, is overexpressed in multiple human cancers, but how USP22 impacts tumorigenesis is not clear. We reported previously that Usp22 loss in mice impacts execution of several signaling pathways driven by growth factor receptors such as ERBB2. To determine whether changes in USP22 expression affects ERBB2-driven tumorigenesis, we introduced conditional overexpression or deletion alleles of Usp22 into mice bearing the MMTV-NIC transgene, which drives both rat ERBB2/NEU expression and Cre recombinase activity from the MMTV promoter resulting in mammary tumor formation. We found that USP22 overexpression in mammary glands did not further enhance primary tumorigenesis in MMTV-NIC female mice, but increased lung metastases were observed. However, deletion of Usp22 significantly decreased tumor burden and increased survival of MMTV-NIC mice. These effects were associated with markedly decreased levels of both Erbb2 mRNA and protein, indicating Usp22 loss impacts MMTV promoter activity. Usp22 loss had no impact on ERBB2 expression in other settings, including MCF10A cells bearing a CMV-driven ERBB2 transgene or in HER2+ human SKBR3 and HCC1953 cells. Decreased activity of the MMTV promoter in MMTV-NIC mice correlated with decreased expression of known regulatory factors, including the glucocorticoid receptor (GR), the progesterone receptor (PR), and the chromatin remodeling factor BRG1. Together our findings indicate that increased expression of USP22 does not augment the activity of an activated ERBB2/NEU transgene, but impacts of Usp22 loss on tumorigenesis cannot be assessed in this model due to unexpected effects on MMTV-driven Erbb2/Neu expression.

中文翻译：

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USP22 过表达无法增加 MMTV-ERBB2 小鼠的肿瘤形成，但功能丧失会影响 MMTV 启动子活性

USP22 去泛素酶是 SAGA 组蛋白修饰复合物的一个组成部分，在多种人类癌症中过度表达，但 USP22 如何影响肿瘤发生尚不清楚。我们之前报道过，小鼠中 Usp22 的缺失会影响由生长因子受体（例如 ERBB2）驱动的多个信号通路的执行。为了确定 USP22 表达的变化是否影响 ERBB2 驱动的肿瘤发生，我们将 Usp22 的条件性过表达或缺失等位基因引入携带 MMTV-NIC 转基因的小鼠中，该转基因驱动大鼠 ERBB2/NEU 表达和 MMTV 启动子的 Cre 重组酶活性，从而产生乳腺肿瘤。肿瘤形成。我们发现乳腺中USP22的过度表达并没有进一步增强MMTV-NIC雌性小鼠的原发性肿瘤发生，但观察到肺转移增加。然而，Usp22 的缺失显着降低了 MMTV-NIC 小鼠的肿瘤负荷并增加了存活率。这些效应与 Erbb2 mRNA 和蛋白质水平显着降低相关，表明 Usp22 丢失影响 MMTV 启动子活性。在其他环境中，Usp22 缺失对 ERBB2 表达没有影响，包括携带 CMV 驱动的 ERBB2 转基因的 MCF10A 细胞或 HER2+ 人 SKBR3 和 HCC1953 细胞。MMTV-NIC 小鼠中 MMTV 启动子活性的降低与已知调节因子表达的降低相关，包括糖皮质激素受体 (GR)、孕激素受体 (PR) 和染色质重塑因子 BRG1。我们的研究结果共同表明，USP22 表达的增加不会增强激活的 ERBB2/NEU 转基因的活性，