The CUG-translated WT1, not AUG-WT1, is an oncogene

Area of Science:

• Cancer Biology
• Molecular Oncology

Background:

• The Wilms' tumor 1 (WT1) gene exhibits contradictory roles, acting as both a tumor suppressor and an oncogene.
• WT1's dual function is poorly understood, hindering therapeutic strategies for WT1-associated cancers.

Purpose of the Study:

• To elucidate the distinct functions of different WT1 protein isoforms.
• To resolve the "chameleon" nature of WT1 in cancer biology.

Main Methods:

• Investigated WT1 protein synthesis initiation sites, focusing on AUG and CUG codons.
• Analyzed the oncogenic and tumor-suppressive activities of augWT1 and cugWT1 isoforms.
• Examined the effects of WT1 isoforms on target genes (c-myc, bcl-2, egfr) and cellular processes (transformation, colony formation).
• Assessed post-translational modifications, including AKT-mediated phosphorylation and proteasomal degradation pathways involving FBXW8.

Main Results:

• Identified a novel N-terminally extended WT1 isoform, cugWT1, initiated from a CUG codon, which is overexpressed in cancers.
• Demonstrated that cugWT1 promotes cell transformation and upregulates oncogenic targets (c-myc, bcl-2, egfr).
• Confirmed that the canonical augWT1 isoform suppresses tumor growth and represses these same oncogenic targets, partly via HDAC1 recruitment.
• Showed that AKT phosphorylates cugWT1, preventing its degradation by FBXW8, thereby stabilizing the oncogenic form.

Conclusions:

• The study resolves the WT1 "chameleon" function by distinguishing the oncogenic cugWT1 from the tumor-suppressive augWT1.
• Findings reveal cugWT1 as a potential therapeutic target in cancers characterized by its overexpression.
• Understanding WT1 isoform-specific functions provides critical insights into cancer development and progression.