VHL and cancer: In cancer, however, several pathways have emerged that stabilize the expression and activity of HIF-1a even in the presence of oxygen, such as through aberrant phosphoinositide 3-kinase (PI3K)/Akt signaling [36], loss of the tumor suppressor VHL [37], expression of lincRNA-p21, which binds to HIF-1a and disrupts its interaction with VHL [38], or overexpression of deubiquitinases [30,39].