Lending an ‘ELPing hand to tumor initiation

Insight from Jeremy Rich

Tumors are aberrant organ systems that develop through cooption of developmental and wound response programs. Wnt signaling represents a central organizing force in organ development and healing, but constitutive Wnt activation initiates and maintains tumor growth. Development of molecular targeted therapies against Wnt has proven challenging because of the diversity of ligands, receptors, and effectors.

In this issue, Ladang et al. discover that ELP3, an enzymatic component of Elongator, promotes Wnt-induced colon tumorigenesis and recovery from injury. As its name implies, the Elongator complex critically regulates transcriptional elongation through RNA polymerase II, but Elongator also functions in translation through tRNA modification, cytoplasmic kinase signaling, and exocytosis. Leveraging previous studies of oncogenic activity of Elongator, the authors found that Wnt induces ELP3 and that ELP3 levels are increased in colon cancers, a cancer commonly associated with Wnt dysregulation. Targeted disruption of ELP3 in the colon ablated Tuft cell generation, but no significant phenotype in colon organization or animal health was detectable at baseline. In contrast, loss of ELP3 severely attenuated tumor initiation and recovery from radiation injury, potentially through translation—not transcriptional—control of SOX9, a master organizer of the endodermal cellular hierarchy.

(A) A healthy intestinal crypt is illustrated in the left panel. Upon inactivation of the Apc gene suppressor (“Oncogenic hit”), Wnt signaling is constitutively activated and triggers adenoma development. Whereas the acetylase ELP3 is dispensable for the maintenance of normal stem cells and intestinal homeostasis, this factor is required for Wnt-dependent tumor initiation and induction of cancer stem cell self-renewal. (B) The inactivation of Apc triggers β-catenin stabilization and consequently drives the expression of Wnt target genes, such as SOX9 and ELP3. ELP3 chemically modifies tRNAs to promote SOX9 translation. As a result, a pool of Lgr5⁺/Dclk1⁺/Sox9⁺ cells efficiently drives Wnt-dependent tumor initiation in the intestine.

The colon undergoes continuous renewal with replacement of the colonic epithelium every seven days on average. Upon injury, like radiation, Wnt signaling is activated to accelerate self-renewal. The current study suggests that Elongator activity is necessary for injury responses in the colon, although future studies may define whether Elongator is sufficient for recovery of the colon and other tissues dependent on Wnt. Conceptually, activating Elongator could accelerate regeneration or improve the efficacy of cell-based therapies. As ELP3 is the catalytic subunit of the histone acetyltransferase elongator complex, its activity may be amenable to disruption through pharmacologic antagonists. Targeting ELP3 in the colon had minimal detrimental effects, suggesting that ELP3 may be an attractive target in Wnt-related cancers, especially in the colon where orally administered therapies could provide locoregional antagonism.