Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation

Cell Death Dis. 2020 Dec 10;11(12):1045. doi: 10.1038/s41419-020-03174-6.

Abstract

Eukaryotic Translation Initiation Factor 5A (EIF5A) is a translation factor regulated by hypusination, a unique posttranslational modification catalyzed by deoxyhypusine synthetase (DHPS) and deoxyhypusine hydroxylase (DOHH) starting from the polyamine spermidine. Emerging data are showing that hypusinated EIF5A regulates key cellular processes such as autophagy, senescence, polyamine homeostasis, energy metabolism, and plays a role in cancer. However, the effects of EIF5A inhibition in preclinical cancer models, the mechanism of action, and specific translational targets are still poorly understood. We show here that hypusinated EIF5A promotes growth of colorectal cancer (CRC) cells by directly regulating MYC biosynthesis at specific pausing motifs. Inhibition of EIF5A hypusination with the DHPS inhibitor GC7 or through lentiviral-mediated knockdown of DHPS or EIF5A reduces the growth of various CRC cells. Multiplex gene expression analysis reveals that inhibition of hypusination impairs the expression of transcripts regulated by MYC, suggesting the involvement of this oncogene in the observed effect. Indeed, we demonstrate that EIF5A regulates MYC elongation without affecting its mRNA content or protein stability, by alleviating ribosome stalling at five distinct pausing motifs in MYC CDS. Of note, we show that blockade of the hypusination axis elicits a remarkable growth inhibitory effect in preclinical models of CRC and significantly reduces the size of polyps in APCMin/+ mice, a model of human familial adenomatous polyposis (FAP). Together, these data illustrate an unprecedented mechanism, whereby the tumor-promoting properties of hypusinated EIF5A are linked to its ability to regulate MYC elongation and provide a rationale for the use of DHPS/EIF5A inhibitors in CRC therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / pathology
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Down-Regulation
  • Eukaryotic Translation Initiation Factor 5A
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lysine / analogs & derivatives*
  • Lysine / metabolism
  • Mice, Nude
  • Open Reading Frames / genetics
  • Oxidoreductases Acting on CH-NH Group Donors / antagonists & inhibitors
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Peptide Initiation Factors / chemistry
  • Peptide Initiation Factors / metabolism*
  • Peptides / metabolism
  • Polyamines / metabolism
  • Protein Biosynthesis
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism*

Substances

  • Peptide Initiation Factors
  • Peptides
  • Polyamines
  • Proto-Oncogene Proteins c-myc
  • RNA-Binding Proteins
  • hypusine
  • Oxidoreductases Acting on CH-NH Group Donors
  • deoxyhypusine synthase
  • Lysine