Hyperactivity of Wnt/ß-catenin signaling has been linked to the development of numerous malignancies, particularly colon cancers. Wnt/ß-catenin signaling also regulates body axis formation in early development. This new study from the Duan lab shows that a new isoform of HIF-3a, an oxygen-regulated transcription factor, negatively regulates Wnt/ß-catenin signaling by promoting the degradation of ß-catenin and its co-factors in the nucleus. Overexpression of HIF-3a2 results in left-right asymmetry defects in zebrafish embryos. This action is independent from HIF-3a's transcriptional activity and is conserved in human cells. These findings uncover a novel mechanism regulating Wnt/ß-catenin signaling and may lead to new therapeutic strategies to suppress Wnt/ß-catenin hyperactivity in colon cancers and other malignancies.
Peng Zhang, Yan Bai, Ling Lu, Yun Li, Cunming Duan, An oxygen-insensitive Hif-3a isoform inhibits Wnt signaling by destabilizing the nuclearß-catenin complex