title: RPL24: a potential therapeutic target whose depletion or acetylation inhibits polysome assembly and cancer cell growth.
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.
authors: Buck Institute for Research on Aging; Novato, CA, USA.
authors: Kathleen A
authors: KA
authors: Wilson-Edell
authors: Buck Institute for Research on Aging; Novato, CA, USA.
authors: Amanuel
authors: A
authors: Kehasse
authors: Buck Institute for Research on Aging; Novato, CA, USA.
authors: Gary K
authors: GK
authors: Scott
authors: Buck Institute for Research on Aging; Novato, CA, USA.
authors: Christina
authors: C
authors: Yau
authors: Buck Institute for Research on Aging; Novato, CA, USA.
authors: Daniel E
authors: DE
authors: Rothschild
authors: Buck Institute for Research on Aging; Novato, CA, USA.
authors: Birgit
authors: B
authors: Schilling
authors: Buck Institute for Research on Aging; Novato, CA, USA. Master of Science in Biology Program; Dominican University; San Rafael, CA, USA.
authors: Bianca S
authors: BS
authors: Gabriel
authors: Buck Institute for Research on Aging; Novato, CA, USA. Master of Science in Biology Program; Dominican University; San Rafael, CA, USA.
authors: Mariya A
authors: MA
authors: Yevtushenko
authors: Buck Institute for Research on Aging; Novato, CA, USA.
authors: Ingrid M
authors: IM
authors: Hanson
authors: Buck Institute for Research on Aging; Novato, CA, USA.
authors: Jason M
authors: JM
authors: Held
authors: Buck Institute for Research on Aging; Novato, CA, USA. Department of Pharmaceutical Chemistry, University of California, San Francisco, CA USA.
authors: Bradford W
authors: BW
authors: Gibson
authors: Buck Institute for Research on Aging; Novato, CA, USA. Oncology-Hematology Division, Department of Medicine, University of California, San Francisco, CA USA.
authors: Christopher C
authors: CC
authors: Benz
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000595:Amino Acid Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011132:Polyribosomes / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012269:Ribosomal Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C109284:EIF6 protein, human; D039642:Eukaryotic Initiation Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012269:Ribosomal Proteins; C036298:ribosomal protein L24; C012589:trichostatin A; D008239:Lysine