RPL24: A potential therapeutic target whose depletion or acetylation inhibits polysome assembly and cancer cell growth

Kathleen A. Wilson-Edell, Amanuel Kehasse, Gary K. Scott, Christina Yau, Daniel E. Rothschild, Birgit Schilling, Bianca S. Gabriel, Mariya A. Yevtushenko, Ingrid M. Hanson, Jason M. Held, Bradford W. Gibson, Christopher C. Benz

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Partial loss of large ribosomal subunit protein 24 (RPL24) function is known to protect mice against Akt or Myc-driven cancers, in part via translational inhibition of a subset of cap(eIF4E)-dependently translated mRNAs. The role of RPL24 in human malignancies is unknown. By analyzing a public dataset of matched human breast cancers and normal mammary tissue, we found that breast cancers express significantly more RPL24 than matched normal breast samples. Depletion of RPL24 in breast cancer cells by >70% reduced cell viability by 80% and decreased protein expression of the eIF4E-dependently translated proteins cyclin D1 (75%), survivin (46%) and NBS1 (30%) without altering GAPDH or beta-tubulin levels. RPL24 knockdown also reduced 80S subunit levels relative to 40S and 60S levels. These effects on expression of eIF4E-dependent proteins and ribosome assembly were mimicked by 2-24 h treatment with the pan-HDACi, trichostatin A (TSA), which induced acetylation of 15 different polysome-associated proteins including RPL24. Furthermore, HDAC6-selective inhibition or HDAC6 knockdown induced ribosomal protein acetylation. Via mass spectrometry, we found that 60S-associated, but not, polysome-associated, RPL24 undergoes HDACi-induced acetylation on K27. Thus, RPL24 K27 acetylation may play a role in ribosome assembly. These findings point toward a novel acetylation-dependent polysome assembly mechanism regulating tumorigenesis.

Original languageEnglish
Pages (from-to)5165-5176
Number of pages12
JournalOncotarget
Volume5
Issue number13
DOIs
StatePublished - 2014

Keywords

  • Breast cancer
  • EIF6
  • HDACs
  • RPL24
  • Ribosome assembly
  • Translation

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