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A small subunit processome protein promotes cancer by altering translation

Oncogene volume 34, pages 4471–4481 (2015)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by a Brain Science Foundation Research Award, the Santos Family Foundation, a Hagerty Fund Research Award, R01 NS062219 from the National Institute of Neurological Disorders and Stroke and an NIH Director’s New Innovator Award (DP2 OD002319) to MDJ.

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Authors and Affiliations

  1. Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    H W Yang, S S Song, L Menon, X Jiang, W Huang, P M Black, R S Carroll & M D Johnson

  2. Center for Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    T-M Kim & P J Park

  3. Program in Neuro-Oncology, Dana Farber/Brigham and Women’s Cancer Center, Boston, MA, USA

    M D Johnson

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  1. H W Yang
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Correspondence to M D Johnson.

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Yang, H., Kim, TM., Song, S. et al. A small subunit processome protein promotes cancer by altering translation. Oncogene 34, 4471–4481 (2015). https://doi.org/10.1038/onc.2014.376

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