TIP60 inhibits metastasis by ablating DNMT1−SNAIL2-driven epithelial-mesenchymal transition program

Zhang, Yanzhou; Krishna, Sudhir; Rajagopalan, Deepa; Tham, Cheng Yong; Abdullah, Lissa Nurrul; Toh, Tan Boon; Gong, Ming; Tan, Tuan Zea; Jadhav, Shweta; Pandey, Amit Kumar; Karnani, Neerja; Chow, Edward Kai‐Hua; Thiery, Jean Paul; Jha, Sudhakar

doi:10.1093/jmcb/mjw038

Cited by 19 publications

(10 citation statements)

References 76 publications

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“…However, the mechanism of the upregulation of Snail as the initial response to Tat treatment is unclear. Further experiments are required to study whether other Tat‐interacting proteins that are involved in Snail expression may be affected by Tat treatment …”

Section: Discussionmentioning

confidence: 99%

“…Further experiments are required to study whether other Tat-interacting proteins that are involved in Snail expression may be affected by Tat treatment. 38 Within the N-terminal region of TIP30, there is an adenosine triphosphate-binding motif driving TIP30 kinase activity, which is required for the phosphorylation of RNA polymerase II and the enhancement of Tat-activated transcription. 15 Additionally, TIP30 contains a highly conserved β-α-β motif, which binds to NADPH and drives TIP30 reductase activity.…”

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confidence: 99%

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Human immunodeficiency virus Tat‐TIP30 interaction promotes metastasis by enhancing the nuclear translocation of Snail in lung cancer cell lines

et al. 2018

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Lung cancer patients with human immunodeficiency virus (HIV) have a poorer prognosis than do patients without HIV infection. HIV1 Tat is a secreted viral protein that penetrates the plasma membrane and interacts with a number of proteins in non‐HIV‐infected cells. The loss of function of Tat‐interacting protein 30 (TIP30) has been linked to metastasis in non‐small cell lung cancer (NSCLC). However, it is unknown how the interaction of HIV1 Tat with TIP30 regulates the metastasis of NSCLC cells. In this study, the overexpression of TIP30 decreased tumor growth factor‐β‐induced epithelial‐to‐mesenchymal transition (EMT) and invasion of NSCLC cells, whereas the knockdown of TIP30 promoted EMT, invasion and stemness. Exposure to recombinant HIV1 Tat proteins promoted EMT and invasion. A mechanistic study showed that the interaction of HIV1 Tat with TIP30 blocked the binding of TIP30 to importin‐β, which is required for the nuclear translocation of Snail. Indeed, the loss of TIP30 promoted the nuclear translocation of Snail. In vivo studies demonstrated that the overexpression of TIP30 inhibited the metastasis of NSCLC cells. In contrast, the coexpression of HIV1 Tat and TIP30 diminished the inhibitory effect of TIP30 on metastasis. Immunohistochemistry confirmed that TIP30 overexpression reduced the nuclear localization of Snail, whereas the coexpression of HIV1 Tat and TIP30 increased nuclear Snail in metastatic tumors. In conclusion, the binding of HIV1 Tat to TIP30 enhanced EMT and metastasis by regulating the nuclear translocation of Snail. Targeting Tat‐interacting proteins may be a potential therapeutic strategy to prevent metastasis in NSCLC patients with HIV infection.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Human immunodeficiency virus Tat‐TIP30 interaction promotes metastasis by enhancing the nuclear translocation of Snail in lung cancer cell lines

et al. 2018

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“…. TIP60 rabbit polyclonal antibody was generated in the lab and reported previously (Frank et al, 2003;Jha et al, 2010;Rajagopalan et al, 2017;Rajagopalan et al, 2018;Subbaiah et al, 2016;Zhang et al, 2016).…”

Section: Antibodiesmentioning

confidence: 99%

TIP60 acetylates H2AZ and regulates doxorubicin-induced DNA damage sensitivity throughRAD51transcription

Lee

Zhang

Magallanes

et al. 2020

Preprint

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TIP60, a lysine acetyltransferase and H2AZ, a histone H2A variant are involved in transcription and DNA repair. Recent studies suggest that H2AZ acetylation is dependent on TIP60. Here, we show that TIP60 acetylates both isoforms of H2AZ in vitro and in cells. Utilizing ChIP-seq and RNA-seq to identify the genes regulated by TIP60-dependent acetylation of H2AZ, we find that TIP60-dependent acetylation of H2AZ correlates with the expression of genes involved in DNA damage repair, amongst several other pathways. In line with this, TIP60-depleted cells exhibit increased sensitivity to the DNA damage-inducing drug doxorubicin. Restoring the expression level of RAD51, one of the genes involved in the DNA damage repair pathway, partially rescues the doxorubicin sensitivity due to TIP60 depletion. Overall, our study uncovers a role for TIP60 in regulating doxorubicin-induced DNA damage sensitivity in a manner dependent on RAD51 transcription. LN, DN, WST, CYT conducted the experiments. KKL, YZ, LN performed protein purification and HAT assay. YZ generated samples for RNA-seq and ChIP-seq, and CYT generated samples for 1 set of RNA-seq data. YZ, KKL, LN, SSB and DR validated RNA-seq results. DR and SSB validated ChIP-seq results. KKL, YZ, DR, SSB and LN performed doxorubicin sensitivity assays. KKL performed cisplatin and camptothecin sensitivity assays. DN performed knockdown in various cell lines. WST attempted some mice experiments. RTM and SSB conducted and, TB and SJ supervised the bioinformatics analysis used in this study. MMH, ADJ, YT, CWJ and DGT helped in the better design of experiments and provided valuable intellectual input. 37

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“…As expected, the inhibitory effect of Tip60 up-regulation on CCA cell growth and invasion was significantly rescued by PI3K/AKT activation. AKT is activated in many human cancers, endowing tumor cells with motile and invasive properties [34]. The PI3K/AKT signaling pathway is also an important intracellular signal transduction pathway, participating in regulation of cell apoptosis and proliferation [35,36].…”

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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TIP60 inhibits metastasis by ablating DNMT1−SNAIL2-driven epithelial-mesenchymal transition program

Cited by 19 publications

References 76 publications

Human immunodeficiency virus Tat‐TIP30 interaction promotes metastasis by enhancing the nuclear translocation of Snail in lung cancer cell lines

Human immunodeficiency virus Tat‐TIP30 interaction promotes metastasis by enhancing the nuclear translocation of Snail in lung cancer cell lines

TIP60 acetylates H2AZ and regulates doxorubicin-induced DNA damage sensitivity throughRAD51transcription

Tip60 Suppresses Cholangiocarcinoma Proliferation and Metastasis via PI3k-AKT

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