RPL24: a potential therapeutic target whose depletion or acetylation inhibits polysome assembly and cancer cell growth
Metrics: PDF 1947 views | HTML 1908 views | ?
Kathleen A. Wilson-Edell1, Amanuel Kehasse1, Gary K. Scott1, Christina Yau1, Daniel E. Rothschild1, Birgit Schilling1, Bianca S. Gabriel1,2, Mariya A. Yevtushenko 1,2, Ingrid M. Hanson1, Jason M. Held1 , Bradford W. Gibson1,3 and Christopher C. Benz 1,4
1 Buck Institute for Research on Aging; Novato, CA, USA
2 Master of Science in Biology Program; Dominican University; San Rafael, CA, USA
3 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA USA
4 Oncology-Hematology Division, Department of Medicine, University of California, San Francisco, CA USA
Christopher C. Benz, email:
Keywords: RPL24, eIF6, ribosome assembly, translation, HDACs, breast cancer
Received: June 4, 2014 Accepted: June 11, 2014 Published: June 12, 2014
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.