The ATPase hCINAP regulates 18S rRNA processing and is essential for embryogenesis and tumour growth

Nat Commun. 2016 Aug 1;7:12310. doi: 10.1038/ncomms12310.

Abstract

Dysfunctions in ribosome biogenesis cause developmental defects and increased cancer susceptibility; however, the connection between ribosome assembly and tumorigenesis remains unestablished. Here we show that hCINAP (also named AK6) is required for human 18S rRNA processing and 40S subunit assembly. Homozygous CINAP(-/-) mice show embryonic lethality. The heterozygotes are viable and show defects in 18S rRNA processing, whereas no delayed cell growth is observed. However, during rapid growth, CINAP haploinsufficiency impairs protein synthesis. Consistently, hCINAP depletion in fast-growing cancer cells inhibits ribosome assembly and abolishes tumorigenesis. These data demonstrate that hCINAP reduction is a specific rate-limiting controller during rapid growth. Notably, hCINAP is highly expressed in cancers and correlated with a worse prognosis. Genome-wide polysome profiling shows that hCINAP selectively modulates cancer-associated translatome to promote malignancy. Our results connect the role of hCINAP in ribosome assembly with tumorigenesis. Modulation of hCINAP expression may be a promising target for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast / pathology
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Colon / pathology
  • Crystallography, X-Ray
  • DNA-Binding Proteins
  • Embryonic Development / genetics*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / genetics*
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Polyribosomes / genetics
  • Polyribosomes / metabolism
  • Prognosis
  • RNA Processing, Post-Transcriptional*
  • RNA, Ribosomal, 18S / metabolism*
  • Survival Analysis

Substances

  • CINAP protein, mouse
  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Ribosomal, 18S
  • TSPYL2 protein, human