Regulation and Destabilization of HIF-1α by ARD1-Mediated Acetylation

Jeong, Joo Won; Bae, Moon Kyoung; Ahn, Mee Young; Kim, Se Hee; Sohn, Tae Kwon; Bae, Myung Ho; Yoo, Mi‐Ae; Song, Eun Joo; Lee, Kong Joo; Kim, Kyu Won

doi:10.1016/s0092-8674(02)01085-1

Cited by 661 publications

(604 citation statements)

References 48 publications

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“…In the presence of oxygen, prolyl hydroxylases (known as prolylhydroxylase-domain protein 1-3), modify Hif-1a and thereby allow it to interact with the von Hippel Lindau (VHL) complex resulting in ubiquitination and proteasomal degradation of Hif-1a (Semenza, 2001). Moreover, O 2 -dependent hydroxylation of Hif-1a by the enzyme factor inhibiting Hif-1 blocks the interaction of Hif-1a with the transcriptional coactivator p300/CBP and therefore inhibits HIF-1 mediated gene transcription under normoxic conditions (Jeong et al, 2002). During hypoxia the rate of asparagine and proline hydroxylation decreases, VHL cannot bind anymore to Hif-1a, and thus the protein remains stable.…”

Section: Introductionmentioning

confidence: 99%

Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

et al. 2006

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Hypoxia inducible factor-1 (HIF-1) is the major transcription factor and key regulator of adoptive responses to hypoxia. Although it usually promotes tumor cell survival under hypoxia, it has also been implied to trigger apoptosis. Although the impact of hypoxia has been extensively studied in many adult solid tumors, its role in most childhood tumors, for example, in rhabdomyosarcoma (RMS) or Ewing sarcoma (ES), has not yet been addressed. Here, we report that hypoxia protects A204 RMS and A673 ES cells against anticancer drug-or tumor necrosis factor-related apoptosis-inducing ligandinduced apoptosis and that Hif-1a plays a key role in conferring apoptosis resistance under hypoxia. Although a functional HIF-1 pathway and proapoptotic proteins such as p53 and Bcl-2/E1B 19 kDa interacting protein 3 were activated under hypoxia in both A204 RMS and A673 ES cells, these cells remained refractory to apoptosis. Concomitant analysis of antiapoptotic proteins revealed that hypoxia induced expression of Bcl-2 and inhibitor of apoptosis proteins (IAP)-2 as well as proteins associated with anaerobic metabolism such as the glucose transporter protein GLUT-1 and the glycolytic enzyme Aldolase A. Specific downregulation of Hif-1a by RNA interference significantly enhanced apoptosis under hypoxia by preventing the hypoxia-mediated increase in GLUT-1 expression without altering expression levels of the antiapoptotic proteins Bcl-2 or cIAP-2. Moreover, glucose deprivation-induced apoptosis of A204 RMS and A673 ES cells was inhibited under hypoxic conditions in a Hif-1a-dependent manner. As GLUT-1 was induced via Hif-1a under hypoxia in A204 RMS and A673 ES, these findings suggest that the Hif-1a-mediated increase in glucose uptake plays an important role in conferring apoptosis resistance. Thus, hypoxia-inducible genes may represent novel targets for therapeutic intervention in some pediatric tumors, which warrants further investigation.

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Section: Introductionmentioning

confidence: 99%

Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

et al. 2006

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“…GST, glutathione-S-transferase; HBx, HBV regulatory protein; HIF-1a, hypoxia-inducible factor-1a; ODD, oxygen-dependent degradation; WT, wild type. 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.…”

Section: Discussionmentioning

confidence: 99%

“…Specific prolyl hydroxylases (PHDs) catalyse the hydroxylation of these proline residues in an oxygen-dependent manner (Brahimi-Horn et al, 2005). Recent investigations suggest that acetyltransferases and histone deacetylases (HDACs) may have a role in the regulation of stability and transcriptional activity of HIF-1a (Jeong et al, 2002;Chang et al, 2006;Yoo et al, 2006).…”

Section: Introductionmentioning

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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“…HDACi can induce HIF-1a degradation by acetylation at Lys532, leading to the interaction with, and ubiquitination by pVHL (Jeong et al, 2002). Further, HDACi can induce HIF-1a degradation in a VHL-independent mechanism .…”

Section: Hdaci Inhibits Angiogenesismentioning

confidence: 99%