pVHL acts as a down-stream target of E2F1 to suppress E2F1 activity

The von Hippel-Lindau (VHL) gene is a well-defined tumor suppressor linked to hereditary cancer syndrome. Although it is well documented that pVHL mediates HIF-1/2α degradation under normoxia conditions, accounting for a major mechanism of pVHL in tumor suppression, it remains elusive whether other HIF-independent functions contribute to pVHL tumor suppressive function. Here, we found that pVHL is a downstream target of E2F1, which harbors E2F1 binding site in its promoter. Moreover, pVHL binds to E2F1 in vitro and in vivo, resulting in inhibition of E2F1 transcriptional activity. Mechanistic studies showed that pVHL binding enhances E2F1 deacetylation. Further immunoprecipitation assays indicated that pVHL interaction diminishes P/CAF and p300 association with E2F1, but enhance Sirt1 binding to E2F1. In addition, upon DNA damage, pVHL is induced. Knockdown of pVHL sensitizes cell to DNA damage-induced apoptosis dependent on E2F1, uncovering a role of pVHL in response to DNA damage. Our findings reveal a novel function of pVHL and demonstrate a negative feedback loop between pVHL and E2F1, which may shed new light on explanation of pVHL role in tumor suppression.
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Signal Source Type: research