Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

J Exp Med. 2015 Nov 16;212(12):2057-75. doi: 10.1084/jem.20142288. Epub 2015 Nov 2.

Abstract

Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Gene Expression / radiation effects
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestines / physiopathology*
  • Intestines / radiation effects
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Organ Culture Techniques
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Regeneration / genetics
  • Regeneration / physiology*
  • Regeneration / radiation effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*

Substances

  • Adenomatous Polyposis Coli Protein
  • Lgr5 protein, mouse
  • Nerve Tissue Proteins
  • Receptors, G-Protein-Coupled
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Wnt Proteins
  • ELP3 protein, human
  • Elp3 protein, mouse
  • Histone Acetyltransferases
  • Dclk1 protein, mouse
  • Protein-Serine-Threonine Kinases