A small subunit processome protein promotes cancer by altering translation.
A small subunit processome protein promotes cancer by altering translation.
复制标题
一种小亚基加工蛋白通过改变翻译来促进癌症。
作者：
Yang,HW;Kim,T-M;Song,SS;Menon,L;Jiang,X;Huang,W;Black,PM;Park,PJ;Carroll,RS;Johnson,MD
核糖体生物发生或翻译的失调可以促进癌症，但其潜在机制仍不清楚。 UTP18 是小亚基加工组的一个组成部分，小亚基加工组是一种核仁多蛋白复合物，其唯一已知的功能是切割前核糖体 RNA，产生 40S 核糖体亚基的 18S 核糖体 RNA 成分。在这里，我们表明 UTP18 还可以改变翻译以促进应激抵抗和生长，并且 UTP18 在癌症中经常获得和过度表达。我们观察到 UTP18 定位于一部分细胞的细胞质，并且血清停药会增加细胞质 UTP18 的定位。细胞质 UTP18 与翻译复合物和 Hsp90 结合，上调含有 IRES 的转录物（如 HIF1a、Myc 和 VEGF）的翻译，从而诱导应激抵抗。 Hsp90 抑制可减少细胞质 UTP18 和 UTP18 诱导的翻译增加。重要的是，UTP18 表达升高与多种癌症的侵袭性增加和生存率降低相关。强制UTP18过度表达会促进转化和肿瘤发生，而UTP18敲低则会抑制这些过程。因此，这种应激适应机制被癌症所选择，其抑制可能代表一个有前途的新治疗靶点。
Dysregulation of ribosome biogenesis or translation can promote cancer, but the underlying mechanisms remain unclear. UTP18 is a component of the small subunit processome, a nucleolar multi-protein complex whose only known function is to cleave pre-ribosomal RNA to yield the 18S ribosomal RNA component of 40S ribosomal subunits. Here, we show that UTP18 also alters translation to promote stress resistance and growth, and that UTP18 is frequently gained and overexpressed in cancer. We observed that UTP18 localizes to the cytoplasm in a subset of cells, and that serum withdrawal increases cytoplasmic UTP18 localization. Cytoplasmic UTP18 associates with the translation complex and Hsp90 to upregulate the translation of IRES-containing transcripts such as HIF1a, Myc and VEGF, thereby inducing stress resistance. Hsp90 inhibition decreases cytoplasmic UTP18 and UTP18-induced increases in translation. Importantly, elevated UTP18 expression correlates with increased aggressiveness and decreased survival in numerous cancers. Enforced UTP18 overexpression promotes transformation and tumorigenesis, whereas UTP18 knockdown inhibits these processes. This stress adaptation mechanism is thus co-opted for growth by cancers, and its inhibition may represent a promising new therapeutic target.