Hypoxia suppresses chemotherapeutic drug-induced p53 Serine 46 phosphorylation by triggering HIPK2 degradation

Moehlenbrink, Jutta; Bitomsky, Nadja; Hofmann, Thomas G.

doi:10.1016/j.canlet.2009.11.016

Cited by 24 publications

(22 citation statements)

References 28 publications

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“…In previous studies, HIPK2 which belongs to a family of co-repressors for homeodomain transcription factors was found to repress the transcription of HIF1α, 18 and HIPK2 degradation induced by hypoxia was associated with chemoresistance in hepatoma cells. 19 In this work, we noticed that HIPK2 mRNA and protein levels significantly increased after knockdown of HDAC5 only under hypoxia condition (Figure 3(c) and (d)). Consistently, hypoxia was required for the reduced HIPK2 expression by overexpressed HDAC5 (Figure 3(e) and (f)).…”

Section: Hdac5 Induces the Transcription Of Hif1α Through Silencing Tsupporting

confidence: 51%

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition

Ye¹,

Fang²,

Gu³

et al. 2017

Tumour Biol.

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Hypoxia plays a critical role in the progression and metastasis of hepatocellular carcinoma by activating the key transcription factor, hypoxia-inducible factor-1. This study aims to identify the novel mechanisms underlying the dysregulation of hypoxia-inducible factor-1α in hepatocellular carcinoma. We found that histone deacetylase 5, a highly expressed histone deacetylase in hepatocellular carcinoma, strengthened the migration and invasion of hepatocellular carcinoma cells under hypoxia but not normoxia condition. Furthermore, histone deacetylase 5 induced the transcription of hypoxia-inducible factor-1α by silencing homeodomain-interacting protein kinase-2 expression, which was also dependent on hypoxia. And then knockdown of hypoxia-inducible factor-1α decreased the expressions of mesenchymal markers, N-cadherin, and Vimentin, as well as matrix metalloproteinases, MMP7 and MMP9; however, the epithelial marker, E-cadherin, increased. Phenotype experiments showed that the migration and invasion of hepatocellular carcinoma cells were impaired by knockdown of histone deacetylase 5 or hypoxia-inducible factor-1α but rescued when eliminating homeodomaininteracting protein kinase-2 in hepatocellular carcinoma cells, which suggested the critical role of histone deacetylase 5-homeodomain-interacting protein kinase-2-hypoxia-inducible factor-1α pathway in hypoxia-induced metastasis. Finally, clinical analysis confirmed the positive correlation between histone deacetylase 5 and hypoxia-inducible factor-1α in hepatocellular carcinoma specimens and a relatively poor prognosis for the patients with high levels of histone deacetylase 5 and hypoxia-inducible factor-1α. Taken together, our findings demonstrated a novel mechanism underlying the crosstalk between histone deacetylase 5 and hypoxia-inducible factor-1 in hepatocellular carcinoma.

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Section: Hdac5 Induces the Transcription Of Hif1α Through Silencing Tsupporting

confidence: 51%

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition

Ye¹,

Fang²,

Gu³

et al. 2017

Tumour Biol.

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“…In vitro translated 35 Slabeled Zyxin was efficiently pulled down by GST-Siah1 ( Fig. 4I), suggesting that the interaction between both proteins is indeed direct.…”

Section: Zyxin Colocalizes and Physically Interacts With Siah-1mentioning

confidence: 92%

“…One important mediator of HIPK2 breakdown is the E3 ubiquitin ligase Siah-1 (6,8,35). Because Zyxin depletion results in proteasome-dependent HIPK2 degradation, we investigated if Zyxin protects HIPK2 from degradation by antagonizing Siah-1 function.…”

Section: Zyxin Inhibits Hipk2 Degradation In a Siah-1-dependent Fashionmentioning

confidence: 99%

Zyxin Is a Critical Regulator of the Apoptotic HIPK2-p53 Signaling Axis

et al. 2011

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HIPK2 activates the apoptotic arm of the DNA damage response by phosphorylating tumor suppressor p53 at serine 46. Unstressed cells keep HIPK2 levels low through targeted polyubiquitination and subsequent proteasomal degradation. Here we identify the LIM domain protein Zyxin as a novel regulator of the HIPK2-p53 signaling axis in response to DNA damage. Remarkably, depletion of endogenous Zyxin, which colocalizes with HIPK2 at the cytoskeleton and in the cell nucleus, stimulates proteasome-dependent HIPK2 degradation. In contrast, ectopic expression of Zyxin stabilizes HIPK2, even upon enforced expression of its ubiquitin ligase Siah-1. Consistently, Zyxin physically interacts with Siah-1, and knock-down of Siah-1 rescues HIPK2 expression in Zyxin-depleted cancer cells. Mechanistically, our data suggest that Zyxin regulates Siah-1 activity through interference with Siah-1 dimerization. Furthermore, we show that endogenous Zyxin coaccumulates with HIPK2 in response to DNA damage in cancer cells, and that depletion of endogenous Zyxin results in reduced HIPK2 protein levels and compromises DNA damage-induced p53 Ser46 phosphorylation and caspase activation. These findings suggest an unforeseen role for Zyxin in DNA damage-induced cell fate control through modulating the HIPK2-p53 signaling axis. Cancer Res; 71(6); 2350-9. Ó2011 AACR.

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“…Other ubiquitin ligases involved in HIPK2 downregulation may take place during hypoxia including WD40-repeat/SOCS box protein WSB-1 (Choi et al, 2008), which is a novel predicted HIF1 target gene, as identified by an integrative genomic approach, upregulated upon hypoxia (Benita et al, 2009); and the RING family member Siah-1, originally identified along with Siah-2 as HIPK2-interacting protein (Winter et al, 2009;Calzado et al, 2009a). As for WSB-1 and Siah-2, Siah-1 depletion by siRNA partially inhibits hypoxia-induced HIPK2 degradation (Moehlenbrink et al, 2010). Interestingly, the p53-inducible Siah-1L protein downregulates HIPK2, suggesting an autoregulatory control of p53 response during hypoxia (Calzado et al, 2009b) similarly to that observed in MDM2 induction after nonsevere DNA damage (Rinaldo et al, 2007b) (Figure 5).…”

Section: Hipk2 Inactivation In Tumors and P53 Dysfunctionmentioning

confidence: 99%

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

et al. 2010

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The p53 protein is the most studied tumor suppressor and the p53 pathway has been shown to mediate cellular stress responses that are disrupted when cancer develops. After DNA damage, p53 is activated as transcription factor to directly induce the expression of target genes involved in cell-cycle arrest, DNA repair, senescence and, importantly, apoptosis. Post-translational modifications of p53 are essential for the activation of p53 and for selection of target genes. The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating its N-terminal serine 46 (Ser46) and facilitating Lys382 acetylation at the C-terminus. HIPK2 is activated by numerous genotoxic agents and can be deregulated in tumors by several conditions including hypoxia. Recent findings suggest that HIPK2 active/inactive protein can affect p53 function in multiple and unexpected ways. This makes p53 as well as HIPK2 interesting targets for cancer therapy. Hence, understanding the role of HIPK2 as p53 activator may provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer.

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Hypoxia suppresses chemotherapeutic drug-induced p53 Serine 46 phosphorylation by triggering HIPK2 degradation

Cited by 24 publications

References 28 publications

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition

Zyxin Is a Critical Regulator of the Apoptotic HIPK2-p53 Signaling Axis

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

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