Histone Deacetylase Inhibitors Repress the Transactivation Potential of Hypoxia-inducible Factors Independently of Direct Acetylation of HIF-α

Fath, Donna M.; Kong, Xianguo; Liang, Dongming; Zhao, Lin; Chou, Andrew; Jiang, Yubao; Fang, Jie; Caro, Jaime; Sang, Nianli

doi:10.1074/jbc.m600456200

Cited by 103 publications

(126 citation statements)

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“…Recent studies have established that HDAC inhibitors decrease HIF activation in tumor cell lines (Kim et al, 2001(Kim et al, , 2007Fath et al, 2006;Kong et al, 2006;Qian et al, 2006), although the mechanism(s) by which HDAC modulate HIF activity remains controversial (Bilton et al, 2006). Our experiments demonstrate that sodium butyrate, an HDAC inhibitor in clinical use (Davie, 2003), improves epithelial-like cell shape and TJ assembly in VHL-defective RCC4 and RCC10 cells and increases expression of E-cadherin, occludin, and claudin 1.…”

Section: Discussionmentioning

confidence: 50%

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Harten

Shukla

Barod

et al. 2009

MBoC

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Epithelial-to-mesenchymal transitions (EMT) are important in renal development, fibrosis, and cancer. Loss of function of the tumor suppressor VHL leads to many features of EMT, and it has been hypothesized that the pivotal mediator is down-regulation of the adherens junction (AJ) protein E-cadherin. Here we show that VHL loss-of-function also has striking effects on the expression of the tight junction (TJ) components occludin and claudin 1 in vitro in VHL-defective clear cell renal cell carcinoma (CCRCC) cells and in vivo in VHL-defective sporadic CCRCCs (compared with normal kidney). Occludin is also down-regulated in premalignant foci in kidneys from patients with germline VHL mutations, consistent with a contribution to CCRCC initiation. Reexpression of E-cadherin was sufficient to restore AJ but not TJ assembly, indicating that the TJ defect is independent of E-cadherin down-regulation. Additional experiments show that activation of hypoxia inducible factor (HIF) contributes to both TJ and AJ abnormalities, thus the VHL/HIF pathway contributes to multiple aspects of the EMT phenotype that are not interdependent. Despite the independent nature of the defects, we show that treatment with the histone deacetylase inhibitor sodium butyrate, which suppresses HIF activation, provides a method for reversing EMT in the context of VHL inactivation. INTRODUCTIONA key characteristic of epithelial surfaces is the formation of specialized intercellular junctions at points of cell-cell contact. It is increasingly appreciated that these junctions have extensive roles beyond their function in cellular cohesion including determination of epithelial permeability and providing inputs modulating proliferation and differentiation. Two important types of intercellular junctions in the kidney epithelium are the tight junction (TJ) and adherens junction (AJ; Tsukita et al., 2001;Conacci-Sorrell et al., 2002;Matter and Balda, 2003). AJs are formed on the basolateral cell membrane and are composed of transmembrane cadherins linked to intracellular catenin proteins (Conacci-Sorrell et al., 2002). AJs are involved in cell-cell adhesion and also regulate ␤-catenin availability (Nelson and Nusse, 2004). TJs are formed on the apical surface of the lateral membrane and are analagous in structure to AJs, with specific transmembrane proteins (occludin and claudins), which are linked to the actin cytoskeleton via intracellular adaptor proteins, the zona occludens (ZO) family of proteins (Tsukita et al., 2001). In addition to its traditional roles in maintaining apical-basal polarity and controlling paracellular permeability the TJ is also now recognized as a signaling hub. TJ regulation of pathways involving raf kinase, rho GTPase, and the Y-box transcription factor ZONAB control important cellular processes such as cell proliferation, gene transcription, and cellular differentiation (Braga, 2002;Matter and Balda, 2003;Gonzalez-Mariscal et al., 2007;Guillemot et al., 2008).VHL is a classical tumor suppressor gene which acts as a gatekeeper i...

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Section: Discussionmentioning

confidence: 50%

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Harten

Shukla

Barod

et al. 2009

MBoC

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“…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. Here, we showed that the ODD domain of HIF-1a was deacetylated in the presence of HBx (Figure 4), and the deacetylation was accompanied by further process of proteasomal degradation, such as binding to PHDs and VHL ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

Oncogene

144

129

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Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1a (HIF-1a) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1a, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1a. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1a. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBxtransgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1a, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

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“…8 This has been demonstrated further in a study by Fath et al showing that HDAC inhibitors repress the transactivation potential of HIF-1α under hypoxic conditions by targeting the HIF-1α/p300 complex. 9 Other members of the HIF-1α coactivation complex SRC-1 and TIF2 have also been found to have histone acetyltransferase activity which enhance the hypoxia-inducible activity of HIF-1α both independently and in synergy with CBP/p300. 10 Histone deacetylase enzymes such as HDAC1, 3 and 7 have also been implicated in the actions of HIF-1α.…”

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confidence: 99%

Epigenetics: The epicenter of the hypoxic response

Watson¹,

Watson²,

McCann³

et al. 2010

Epigenetics

150

125

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Histone Deacetylase Inhibitors Repress the Transactivation Potential of Hypoxia-inducible Factors Independently of Direct Acetylation of HIF-α

Cited by 103 publications

References 71 publications

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin

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

Epigenetics: The epicenter of the hypoxic response

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