p53-paralog DNp73 oncogene is repressed by IFNα/STAT2 through the recruitment of the Ezh2 polycomb group transcriptional repressor

Testoni, Barbara; Schinzari, Valeria; Guerrieri, F.; Gerbal‐Chaloin, Sabine; Blandino, Giovanni; Levrero, Massimo

doi:10.1038/onc.2010.635

Cited by 29 publications

(27 citation statements)

References 48 publications

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“…(24) Interferon-a ⁄ signal transducer and activator of transcription 2 could suppress oncogenic p53-paralog DNp73 expression through the recruitment of the EZH2 polycomb group transcriptional repressor in liver cancer cells. (25) Our results also identified ADRB2, DAB2IP, CDH1, and p16 as PRC2 target genes regulated by EZH2-mediated epigenetic alterations in a dosedependent manner in hepatoma cells after sorafenib treatment. As ADRB2, DAB2IP, CDH1, and p16 have been reported to be involved in EZH2-mediated tumorigenesis, (43)(44)(45)(46) the potential functional significance of these EZH2-silenced genes awaits further investigation in hepatocarcinogenesis.…”

Section: Discussionsupporting

confidence: 69%

“…(12)(13)(14)(15)(16)(17) Given the crucial putative oncogenic function of EZH2 in hepatocarcinogenesis, (18)(19)(20)(21)(22)(23)(24)(25) epigenetic modulators directing EZH2, such as 3-deazaneplanocin A (DZNep), might be used as promising therapeutic agents against liver cancer.…”

mentioning

confidence: 99%

“…(10,11) Overexpression of EZH2 has been implicated in tumorigenesis of malignancies derived from prostate, breast, skin, bladder, stomach, liver, and other organs. (12)(13)(14)(15)(16)(17) Given the crucial putative oncogenic function of EZH2 in hepatocarcinogenesis, (18)(19)(20)(21)(22)(23)(24)(25) epigenetic modulators directing EZH2, such as 3-deazaneplanocin A (DZNep), might be used as promising therapeutic agents against liver cancer. (26,27) However, little is known about the potential significance of epigenome alterations mediated by EZH2 in liver cancer after sorafenib treatment.…”

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confidence: 99%

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Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog 2

Wang¹,

Zhu

et al. 2013

Cancer Science

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Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes that regulate cancer cell growth and survival. It is overexpressed in hepatocellular carcinoma (HCC) with a clinical significance that remains obscure. Sorafenib, a multikinase inhibitor, has been used as a first-line therapeutic drug and shown clinical efficiency for advanced-stage HCC patients. In the present study, we found that sorafenib lowered the protein level of EZH2 through accelerating proteasome-mediated EZH2 degradation in hepatoma cells. Overexpression of EZH2 reversed sorafenibinduced cell growth arrest, cell cycle arrest, and cell apoptosis dependent on histone methyltransferase activity in hepatoma cells. More importantly, shRNA-mediated EZH2 knockdown or EZH2 inhibition with 3-deazaneplanocin A treatment promoted sorafenib-induced hepatoma cell growth arrest and apoptosis. Sorafenib altered the hepatoma epigenome by reducing EZH2 and H3K27 trimethylation. These results revealed a novel therapeutic mechanism underlying sorafenib treatment in suppressing hepatoma growth and survival by accelerating EZH2 degradation. Genetic deletion or pharmacological ablation of EZH2 made hepatoma cells more sensitive to sorafenib, which helps provide a strong framework for exploring innovative combined therapies for advanced-stage HCC patients. (Cancer Sci 2013; 104: 750-759) P rimary liver cancer, predominantly hepatocellular carcinoma (HCC), is a major public health problem worldwide and the third most common cause of cancer-related mortality globally.(1) One of the main reasons for the high mortality rate in patients with HCC is the lack of effective therapeutic options, especially for those with advanced disease.(2) Potentially curative therapies like surgical resection, transplantation, and percutaneous ablation are only available to limited patients with early HCC.(3) Moreover, the majority of patients with HCC present with advanced disease due to the asymptomatic nature of early HCC, lack of awareness, and poorly defined clinical screening strategies.(4) The paucity of effective and well-tolerated treatments for advanced HCC highlights the desperate need for new therapeutic approaches for this deadly disease.The absence of standard systemic therapy for patients with advanced HCC has changed with the recent positive randomized controlled trial testing sorafenib, which represents a breakthrough in the management of this neoplasm.(5) The unprecedented results of a recently published phase III clinical trial show that sorafenib significantly improves survival and time to progression in patients with advanced HCC.(5) Unfortunately, less than half of patients with advanced-stage HCC benefit from these therapies, and the benefits are transient resulting from quickly acquired adaptive resistance to sorafenib treatment.(6) These benefits and challenges highlight the importance of underlying molecular mechanism exploration for sorafenib treatment and novel oncogenic mechanism i...

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Section: Discussionsupporting

confidence: 69%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog 2

Wang¹,

Zhu

et al. 2013

Cancer Science

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“…Indeed, we have recently reported that the recruitment of a P-STAT2 containing ISGF3 complex is required for transcriptional repression of the DNp73 promoter in response to IFN␣ (58). 26% of our repressed genes recruit both STAT2 and P-STAT2 after IFN␣ treatment, thus behaving as the DNp73 promoter.…”

Section: Discussionmentioning

confidence: 80%

Chromatin Dynamics of Gene Activation and Repression in Response to Interferon α (IFNα) Reveal New Roles for Phosphorylated and Unphosphorylated Forms of the Transcription Factor STAT2

Testoni

Völlenkle

Guerrieri

et al. 2011

Journal of Biological Chemistry

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Signal transducer and activator of transcription 2 (STAT2), the critical component of type I interferons signaling, is a prototype latent cytoplasmic signal-dependent transcription factor. Activated tyrosine-phosphorylated STAT2 associates with STAT1 and IRF9 to bind the ISRE elements in the promoters of a subset of IFN-inducible genes (ISGs). In addition to activate hundreds of ISGs, IFN␣ also represses numerous target genes but the mechanistic basis for this dual effect and transcriptional repression is largely unknown. We investigated by ChIP-chip the binding dynamics of STAT2 and "active" phospho(P)-STAT2 on 113 putative IFN␣ direct target promoters before and after IFN␣ induction in Huh7 cells and primary human hepatocytes (PHH). STAT2 is already bound to 62% of our target promoters, including most "classical" ISGs, before IFN␣ treatment. 31% of STAT2 basally bound promoters also show P-STAT2 positivity. By correlating in vivo promoter occupancy with gene expression and changes in histone methylation marks we found that: 1) STAT2 plays a role in regulating ISGs expression, independently from its phosphorylation; 2) P-STAT2 is involved in ISGs repression; 3) "activated" ISGs are marked by H3K4me1 and H3K4me3 before IFN␣; 4) "repressed" genes are marked by H3K27me3 and histone methylation plays a dominant role in driving IFN␣-mediated ISGs repression.Interferons are pleiotropic cytokines induced upon virus infection and other stimuli to modulate host immune response and are classified as type I interferon ␣ and ␤ (IFN␣ and IFN␤), 3 type II (IFN␥), and the recently discovered type III (IFN) (1-3)). Interferons exert their function by phosphorylating latent transcription factors belonging to the signal transducer and activator of transcription (STAT) family after a signaling cascade, which begins with the binding of interferon to their membrane receptors and involves Janus kinases (JAKs). Receptor dimerization or oligomerization leads to Jak apposition and the trans-phosphorylation on tyrosine residues that releases their intrinsic catalytic activity. Tyrosine-phosphorylated cytokine-receptor cytoplasmic domains then provides binding sites for the Src homology-2 (SH2) domain of the STAT proteins, which are recruited to the JAKs and phosphorylated on a single tyrosine residue (Tyr-689 in the case of STAT2). The interaction between phosphorylated-SH2 domains on STAT proteins leads to homo-or hetero-dimerization and nuclear translocation (4 -6). STAT2 Tyr-689 and STAT1 Tyr-701 can also be phosphorylated by non-receptor TKs, including SRC and ABL in the absence of ligand-induced receptor signaling (7). STAT dimers directly activate genes containing the IFN␥ activation site (GAS) element, while the association of STATs with the DNA-binding protein interferon regulatory factor (IRF) 9 expands the range of DNA response elements that can be targeted by the JAK-STAT pathway to interferon-stimulate response element (ISRE) and IRF response element (IRE) (8). Un-phosphorylated STAT2 binds IRF9 and constitutively shuttles i...

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“…In response to IFN-a, STAT2 mediates repression of DNp73 (a transrepressor of p53) resulting in apoptotic death in hepatoma cells (Testoni et al, 2011b). Similarly, about one-quarter of the IFN-inducible genes found to be repressed following IFN-a treatment recruited both STAT2 and pSTAT2 to the promoter regions.…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways

Hernandez

Elahi

Clark

et al. 2015

DNA and Cell Biology

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1HPP1, a novel tumor suppressive epidermal growth factor (EGF)-like ligand, mediates its effects through signal transducer and activators of transcription (STAT) activation. We previously demonstrated the importance of STAT1 activation for HPP1 function; however the contribution of STAT2 remains unclear. We sought to delineate the components of JAK-STAT-interferon (IFN) signaling specifically associated with HPP1s biological effects. Using stable HPP1-HCT116 transfectants, expression analyses were performed by polymerase chain reaction (PCR)/western blotting while expression knockdowns were achieved using siRNA. Growth parameters evaluated included proliferation, cell cycle distribution, and anchorage-independent growth. STAT dimerization, translocation, and DNA binding were examined by reporter assays, fluorescent microscopy, and chromatin immunoprecipitation (ChIP), respectively. Forced expression of HPP1 in colon cancer cell lines results in the upregulation of total and activated levels of STAT2. We have also determined that JAK1 and JAK2 are activated in response to HPP1 overexpression, and are necessary for subsequent STAT activation. Overexpression of HPP1 was associated with significant increases in STAT1:STAT1 ( p = 0.007) and STAT1:STAT2 ( p = 0.036) dimer formation, as well as subsequent nuclear translocation. By ChIP, binding of activated STAT1 and STAT2 to the interferon-signaling regulatory element promoter sites of the selected genes, protein kinase RNA-activated (PKR), IFI44, and OAS1 was demonstrated. STAT2 knockdown resulted in partial abrogation of HPP1s growth suppressive activity with increased proliferation ( p < 0.0001), reduced G1/G0 phase cell cycle fraction, and a restoration of growth potential in soft agar ( p < 0.01). Presumably as a consequence of upregulation of IFN signaling elements, HPP1 overexpression resulted in an acquisition of exogenous IFN sensitivity. Physiologic doses of IFN-a resulted in a significant reduction in proliferation ( p < 0.001) and increase in G1/G0 cell cycle arrest in HPP1 transfectants. STAT2 is necessary for HPP1-associated growth suppression, and mediates these effects through activation of IFN-a pathways. Given the interest in therapeutic targeting of oncogenic erbB proteins, further understanding of HPP1s role as a tumor suppressive EGF-like ligand is warranted.

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p53-paralog DNp73 oncogene is repressed by IFNα/STAT2 through the recruitment of the Ezh2 polycomb group transcriptional repressor

Cited by 29 publications

References 48 publications

Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog 2

Sorafenib suppresses growth and survival of hepatoma cells by accelerating degradation of enhancer of zeste homolog 2

Chromatin Dynamics of Gene Activation and Repression in Response to Interferon α (IFNα) Reveal New Roles for Phosphorylated and Unphosphorylated Forms of the Transcription Factor STAT2

The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways

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