Transcriptional activation of hypoxia-inducible factor-1α by HDAC4 and HDAC5 involves differential recruitment of p300 and FIH-1

Abstract 

The interplay between hypoxia-inducible factor-1α (HIF-1α) and histone deacetylase (HDACs) have been well studied; however, the mechanism of cross-talk is unclear. Here, we investigated the roles of HDAC4 and HDAC5 in the regulation of HIF-1α function and its associated mechanisms. HDAC4 and HDAC5 enhanced transactivation by HIF-1α without stabilizing HIF-1α. HDAC4 and HDAC5 physically associated with HIF-1α through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1). In the presence of these HDACs, binding of HIF-1α to FIH-1 decreased, whereas binding to p300 increased. These results indicate that HDAC4 and HDAC5 increase the transactivation function of HIF-1α by promoting dissociation of HIF-1α from FIH-1 and association with p300.

Structured summary:

MINT-6802187:

HIF1 alpha (uniprotkb:Q16665) physically interacts (MI:0218) with FIH1 (uniprotkb:Q9NWT6) by anti bait coimmunoprecipitation (MI:0006)

MINT-6802058:

HIF1 alpha (uniprotkb:Q16665) physically interacts (MI:0218) with HDAC4 (uniprotkb:P56524) by pull down (MI:0096)

MINT-6802021:

HIF1 alpha (uniprotkb:Q61221) physically interacts (MI:0218) with HDAC4 (uniprotkb:P56524) by anti bait coimmunoprecipitation (MI:0006)

MINT-6802036:

HIF1 alpha (uniprotkb:Q61221) physically interacts (MI:0218) with HDAC5 (uniprotkb:Q9UQL6) by anti bait coimmunoprecipitation (MI:0006)

MINT-6802102:

HIF1 alpha (uniprotkb:Q16665) physically interacts (MI:0218) with HDAC5 (uniprotkb:Q9UQL6) by pull down (MI:0096)

MINT-6802121, MINT-6802156:

P300 (uniprotkb:Q09472) physically interacts (MI:0218) with HIF1 alpha (uniprotkb:Q16665) by anti bait coimmunoprecipitation (MI:0006)

Abbreviations: HIF-1, hypoxia-inducible factor-1, ODD, oxygen-dependent degradation, FIH-1, factor inhibiting HIF-1, HDAC, histone deacetylase, HRE, hypoxia-response element, C-TAD, C-terminal activating domain, ID, inhibitory domain, TSA, trichostatin A, pVHL, von Hippel–Lindau, RT-PCR, reverse transcriptase-polymerase chain reaction, GFP, green fluorescent protein, GST, glutathione S-transferase, si-RNA, small interfering-RNA, DFO, desferroxamine

Keywords: HIF-1α, HDAC, FIH, p300