Fig. 5

HUWE1 under hypoxic stress. HIF1α is a labile protein under noromoxia but the HIF1α protein is stabilized under hypoxia via HUWE1. The deubiquitinase, HAUSP, is K63-polyubiquitinated by HUWE1 under hypoxia. K63-polyubiquitinated HAUSP has the enhanced deubiquitinase activity to stabilize HIF-1α. Moreover, K63-polyubiquitinated HAUSP anchors HIF-1α, CBP, the mediator complex, and the super-elongation complex to enhance the gene transcription activity initiated by HIF-1α, thereby increasing hypoxia-associated tumor aggressiveness