A Bivalent Role of TIP60 Histone Acetyl Transferase in Human Cancer

Judes, Gaëlle; Rifaï, Khaldoun; Ngollo, Marjolaine; Daures, Marine; Bignon, Yves‐Jean; Penault‐Llorca, Frédérique; Bernard‐Gallon, Dominique

doi:10.2217/epi.15.76

Cited by 67 publications

(55 citation statements)

References 104 publications

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“…Previous studies have paradoxically characterized NuA4 as both a tumor suppressor and an oncogene (Gorrini et al 2007;Judes et al 2015). Maintenance of proper cell cycle gene expression may in part underlie some roles for NuA4 in cancer, while others may be due to its roles in DNA damage signaling (Squatrito et al 2006).…”

Section: Nua4 and Cancermentioning

confidence: 99%

Section: The Nua4 Complexmentioning

confidence: 99%

“…However, the NuA4 complex also acts as an essential repressor of gene expression in certain contexts, such as embryonic stem cells (Fazzio et al 2008;Chen et al 2013), and can promote closed chromatin formation in flies (Qi et al 2006). Furthermore, NuA4 components paradoxically act as both tumor suppressors and oncogenes, leaving their positive vs. negative roles in cell cycle control unresolved (Sapountzi et al 2006;Judes et al 2015).Several studies suggest roles for NuA4 and H2Av in regulation of E2F target genes and genetic interactions with DREAM/MMB components (Ceol and Horvitz 2004;Lu et al 2007;DeBruhl et al 2013;Latorre et al 2015). Mammalian studies implicate Tip60/NuA4 as a transcriptional activator of E2F target genes, whereas a subset of NuA4 components in Drosophila cell culture were shown to repress E2F transcriptional targets (Lu et al 2007).…”

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confidence: 99%

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Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Flegel¹,

Grushko²,

Bolin³

et al. 2016

Genetics

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Robust and synchronous repression of E2F-dependent gene expression is critical to the proper timing of cell cycle exit when cells transition to a postmitotic state. Previously NuA4 was suggested to act as a barrier to proliferation in Drosophila by repressing E2F-dependent gene expression. Here we show that NuA4 activity is required for proper cell cycle exit and the repression of cell cycle genes during the transition to a postmitotic state in vivo. However, the delay of cell cycle exit caused by compromising NuA4 is not due to additional proliferation or effects on E2F activity. Instead NuA4 inhibition results in slowed cell cycle progression through late S and G2 phases due to aberrant activation of an intrinsic p53-independent DNA damage response. A reduction in NuA4 function ultimately produces a paradoxical cell cycle gene expression program, where certain cell cycle genes become derepressed in cells that are delayed during the G2 phase of the final cell cycle. Bypassing the G2 delay when NuA4 is inhibited leads to abnormal mitoses and results in severe tissue defects. NuA4 physically and genetically interacts with components of the E2F complex termed Drosophila, Rbf, E2F and Myb/Multi-vulva class B (DREAM/MMB), and modulates a DREAM/MMB-dependent ectopic neuron phenotype in the posterior wing margin. However, this effect is also likely due to the cell cycle delay, as simply reducing Cdk1 is sufficient to generate a similar phenotype. Our work reveals that the major requirement for NuA4 in the cell cycle in vivo is to suppress an endogenous DNA damage response, which is required to coordinate proper S and G2 cell cycle progression with differentiation and cell cycle gene expression.KEYWORDS DNA damage; proliferation; H2Av; cell cycle checkpoint; cell cycle exit A conserved eukaryotic transcriptional oscillator controls cell cycle gene expression in proliferating cells and underlies the well-studied Cyclin/Cdk cell cycle protein oscillator (Orlando et al. 2008;Oikonomou and Cross 2010). In metazoans, this oscillator depends upon transcriptional activation of several hundred cell cycle genes, initiated by E2F transcription factor complexes followed by E2F inhibition (or degradation) (Shibutani et al. 2008;Zielke et al. 2011;Sadasivam and Decaprio 2013). This generates an oscillation of chromatin opening and closing at cell cycle genes that is thought to properly coordinate G1/S and G2/M gene expression as well as the transition to a noncycling state (Litovchick et al. 2007(Litovchick et al. , 2011Forristal et al. 2014). Disruption of this coordination can affect cell cycle progression by causing inappropriate gene expression (Reis and Edgar 2004;Wen et al. 2008;Forristal et al. 2014). While the oscillation of E2F activity is required for robust cell cycle gene expression Korenjak et al. 2012), E2F complexes are not absolutely essential for cell cycle progression or timely cell cycle exit in Drosophila (Frolov et al. 2001(Frolov et al. , 2005. In the absence of E2F activity there must be E2F-independ...

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Section: Nua4 and Cancermentioning

confidence: 99%

Section: The Nua4 Complexmentioning

confidence: 99%

mentioning

confidence: 99%

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Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Flegel¹,

Grushko²,

Bolin³

et al. 2016

Genetics

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“…Tip60 has been shown to remodel chromatin in several diseases, including several cancers such as lymphoma, melanoma, breast, colon, and lung cancer [28]. Many studies have shown that Tip60 may function as a tumor suppressor [29,30]. Hu et al reported that during the blastocyst stage of development, lack of Tip60 promoted embryo lethality, showing that Tip60 is an essential gene [31].…”

Section: Tip60 Attenuated the Proliferation And Metastasis Of Cca Celmentioning

confidence: 99%

Tip60 Suppresses Cholangiocarcinoma Proliferation and Metastasis via PI3k-AKT

Zhang¹,

Han²,

Shao³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Aberrant expression of Tip60 is associated with progression in many cancers. However, the role of Tip60 in cancer progression remains contradictory. The aim of this study was to investigate the clinical significance, biological functions and underlying mechanisms of Tip60 deregulation in cholangiocarcinoma (CCA) for the first time. Methods: Quantitative real-time PCR (QRT-PCR), western blotting and immunohistochemistry staining (IHC) were carried out to measure Tip60 expression in CCA tissues and cell lines. Kaplan–Meier analysis and the log-rank test were used for survival analysis. In vitro, cell proliferation was evaluated by flow cytometry and CCK-8, colony formation, and EDU assays. Migration/ invasion was evaluated by trans-well assays. Phosphokinase array was used to confirm the dominant signal regulated by Tip60. Tumor growth and metastasis were demonstrated in vivo using a mouse model. Results: Tip60 was notably downregulated in CCA tissues, which was associated with greater tumor size, venous invasion, and TNM stage. Down-regulation of Tip60 was associated with tumor progression and poorer survival in CCA patients. In vitro and in vivo studies demonstrated that Tip60 suppressed growth and metastasis throughout the progression of CCA. We further identified the PI3K/AKT pathway as a dominant signal of Tip60 and suggested that Tip60 regulated CCA cell proliferation and metastasis via PT3K-AKT pathway. Pearson analysis revealed that PTEN was positively correlated with the Tip60 level in CCA tissues. Conclusion: Tip60, as a tumor suppressor in CCA via the PI3K/AKT pathway, might be a promising therapeutic target or prognostic marker for CCA.

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“…Additionally, Tip60 played a role as a co-activator to interact with many steroid hormone receptors, such as the androgen receptor (AR) [15], that participate in the occurrence and development of prostate cancer. Other research indicated that Tip60 could facilitate AR acetylation to improve its transcriptional activity [16][17][18]. Furthermore, the expression of Tip60 was increased significantly in clinical prostate cancer tissues and castration-resistant prostate cancer cells, and its expression level was closely related with progression of the disease [19].…”

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confidence: 97%

Tip60 is associated with resistance to X‐ray irradiation in prostate cancer

Xie

Wang

et al. 2017

FEBS Open Bio

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Tip60, an oncogene, accelerates cell growth by regulating androgen receptor translocation into the nucleus in prostate cancer. However, the mechanism of Tip60 in the response of prostate cancer to radiotherapy, and radioresistance, has not been studied. Using human prostate cancer samples and two human prostate cancer cell lines ( LNC aP and DU 145), Tip60 protein expression and the acetylation of ataxia telangiectasia mutant ( ATM ) were analysed by western blotting and immunoprecipitation. Tip60 was downregulated with small interfering RNA . Cells were irradiated using X‐rays at 0.25 Gy·min −1 . Cell viability was assessed by the MTT assay. The expression of Tip60 protein was increased in radioresistant prostate cancer tissues in comparison with radiosensitive tissues, which was also confirmed in both irradiated DU 145 and LNC aP cells. Furthermore, the acetylation of ATM was also upregulated in a time‐dependent manner after irradiation of both DU 145 and LNC aP cells. Additionally, depletion of Tip60 decreased the survival of LNC aP and DU 145 cells by inducing apoptosis, reduced the acetylation of ATM and decreased the expression of phosphorylated ATM , Chk2 and cdc25A in both DU 145 and LNC aP cells after X‐ray irradiation. The results of this study demonstrated that the expression of Tip60 may be related to the radioresistance of prostate cancer and could serve as a promising predictive factor for prostate cancer patients receiving radiotherapy.

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A Bivalent Role of TIP60 Histone Acetyl Transferase in Human Cancer

Cited by 67 publications

References 104 publications

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Tip60 Suppresses Cholangiocarcinoma Proliferation and Metastasis via PI3k-AKT

Tip60 is associated with resistance to X‐ray irradiation in prostate cancer

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