HIF1A and neoplasm: This disrupts VHL ability to target HIF1α for degradation, and suggests that the oxygen-dependent recognition and binding of HIF1α by VHL might be precisely timed in that PIASy affects the engagement of VHL to either ECV E3 ubiquitin complex or other protein complex, thereby establishing a critical role for PIASy to promote the SUMOylation and oligomerization of VHL in a temporally coordinated manner, thus leading to inactivation of VHL function as a tumor suppressor in a HIFα-dependent and independent manner during hypoxia.