Histone Deacetylase Inhibitors Induce VHL and Ubiquitin-Independent Proteasomal Degradation of Hypoxia-Inducible Factor 1α

Abstract

Adaptation to hypoxic microenvironment is critical for tumor survival and metastatic spread. Hypoxiainducible factor 1␣ (HIF-1␣) plays a key role in this adaptation by stimulating the production of proangiogenic factors and inducing enzymes necessary for anaerobic metabolism. Histone deacetylase inhibitors (HDACIs) produce a marked inhibition of HIF-1␣ expression and are currently in clinical trials partly based on their potent antiangiogenic effects. Although it has been postulated that HDACIs affect HIF-1␣ expression by enhancing its interactions with VHL (von Hippel Lindau), thus promoting its ubiquitination and degradation, the actual mechanisms by which HDACIs decrease HIF-1␣ levels are not clear. Here, we present data indicating that HDACIs induce the proteasomal degradation of HIF-1␣ by a mechanism that is independent of VHL and p53 and does not require the ubiquitin system. This degradation pathway involves the enhanced interaction of HIF-1␣ with HSP70 and is secondary to a disruption of the HSP70/HSP90 axis function that appears mediated by the activity of HDAC-6.

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

“…Jeong et al, 2002;Qian et al, 2006), the acetylation hypothesis remains controversial since human ARD1 does not, at least directly, acetylate HIF1a (Arnesen et al, 2005;Bilton et al, 2005Bilton et al, , 2006Fisher et al, 2005;Murray-Rust et al, 2006). Instead, diverse other mechanisms have been proposed for the HDAC inhibitor-induced HIF-1 regulation; Kong et al (2006) showed that HDAC inhibitors induced the proteasomal degradation of HIF-1a by interacting with HSP70 and thereby disrupted the HSP70/HSP90 axis function. In the other hand, Fath et al (2006) reported that acetylation regulated HIF-1 function by targeting the HIF-1a/p300 complex, not by directly targeting HIF-1a.…”

TBP-1 protects the human oncosuppressor p14ARF from proteasomal degradation

“…Furthermore, the entire 19S subunit seems to exist in a dynamic equilibrium with the 20S catalytic subunit that possesses the ubiquitin-independent proteolytic functions and is clearly involved in the degradation of unubiquitinated proteins. Although most cellular proteins degraded in the proteasome are ubiquitinated, proteins such as ornithine decarboxylase, the Cdk inhibitor p21, Hif1a, members of the Rb family of tumor suppressors, p53 and p73 (Sdek et al, 2005;Kong et al, 2006) can be directed to the proteasome without prior ubiquitination. In many cases, if a protein can be delivered to the proteasome in a denatured or partially unfolded state, ubiquitination should not be required for its degradation.…”

“…The accepted physiological form of the proteasome is composed by the 20S core particle (the catalytic subunit) and two 19S regulatory caps that can dynamically associate in an assemble/disassembly cycle. A growing body of evidences is pointing to mechanisms of ubiquitin-independent proteasome degradation that appear to be widespread and physiologically important in higher eukaryotes (Sdek et al, 2005;Kong et al, 2006). In this context, the 20S proteasome subunit plays the major role being clearly involved in degradation of unubiquitinated proteins.…”

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

“…Some of these effects may be indirect and attributed to the activity of HDAC6 as a regulator of HSP90 chaperone functions Murphy et al, 2005;Hurst et al, 2006;Kong et al, 2006).…”