Liu S, Guo R, Xu H, Yang J, Luo H, Yeung SJ, Li K, Lee MH, Yang R

A hypoxic microenvironment contributes to tumor progression, with hypoxia-inducible factor-1? (HIF-1?) being a critical regulator. We have reported that 14-3-3? is negatively associated with HIF-1? expression; however, its role in hypoxia-induced tumor progression remains poorly characterized. Here we show that 14-3-3? suppresses cancer hypoxia-induced metastasis and angiogenesis in colorectal cancer ...

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(CRC). 14-3-3? opposes HIF-1? expression by regulating the protein stability of HIF-1?, thereby decreasing HIF-1? transcriptional activity and suppressing tumor progression. Mechanistic studies show that the 14-3-3?-interacting protein neural precursor cell-expressed developmentally down-regulated 4-like (NEDD4L) is an E3 ligase that targets HIF-1?. 14-3-3? promotes the binding of S448-phosphorylated NEDD4L to HIF-1?, thereby enhancing HIF-1? poly-ubiquitination and subsequent proteasome-mediated degradation. Consistent with this anti-tumorigenic function for 14-3-3?, low 14-3-3? expression levels correlate with poor CRC patient survival, and 14-3-3? enhances the response of CRC to bevacizumab. These results reveal an important mechanism for 14-3-3? in tumor suppression through HIF-1? regulation.

Date: Aug. 29, 2023

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