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Live-imaging of Breast Epithelial Cell Migration After the Transient Depletion of TIP60
Published on: December 7, 2017
TIP60 inhibits metastasis by ablating DNMT1-SNAIL2-driven epithelial-mesenchymal transition program
Yanzhou Zhang1, Vanitha Krishna Subbaiah1, Deepa Rajagopalan1,2
1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Abstract:
HIV-Tat-interacting protein of 60 kDa (TIP60) is a lysine acetyltransferase and known to be downregulated in multiple cancers. Among various signalling pathways, TIP60 is implicated in regulating epithelial-mesenchymal transition (EMT). Here, we show that TIP60 expression abrogates cell migration and metastatic potential of breast cancer cells using in vitro and in vivo models. Mechanistically, we show that this is through its ability to destabilize DNMT1 and inhibit SNAIL2 function (SNAIL2-mediated EMT/cell migration). Depletion of TIP60 stabilizes DNMT1 and increases SNAIL2 levels, resulting in EMT. Recruitment of DNMT1 to the SNAIL2 targets in the absence of TIP60 increases DNA methylation on their promoter region and further represses the expression of epithelial markers. In pathophysiological scenario, we find TIP60 to be significantly downregulated in breast cancer patients with poor overall survival and disease-free survival prognoses. These data suggest that levels of TIP60 can be a prognostic marker of breast cancer progression and stabilization of TIP60 could be a promising strategy to treat cancers.
Insights
HIV-Tat-interacting protein of 60 kDa (TIP60) downregulation promotes breast cancer metastasis by stabilizing DNMT1 and increasing SNAIL2. Restoring TIP60 may offer a novel cancer treatment strategy.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- HIV-Tat-interacting protein of 60 kDa (TIP60) is a lysine acetyltransferase implicated in cancer.
- TIP60 plays a role in regulating epithelial-mesenchymal transition (EMT), a process crucial for cancer metastasis.
Purpose of the Study:
- To investigate the role of TIP60 in breast cancer cell migration and metastasis.
- To elucidate the molecular mechanisms by which TIP60 affects EMT and cancer progression.
Main Methods:
- In vitro and in vivo models of breast cancer were utilized.
- Investigated the interaction between TIP60, DNMT1, and SNAIL2.
- Analyzed DNA methylation patterns and gene expression of epithelial markers.
Main Results:
- TIP60 expression inhibited breast cancer cell migration and metastasis.
- TIP60 destabilizes DNMT1 and inhibits SNAIL2, thereby suppressing EMT.
- TIP60 depletion leads to DNMT1 stabilization, increased SNAIL2, and enhanced EMT.
- DNMT1 recruitment to SNAIL2 targets in TIP60-depleted cells increases DNA methylation and represses epithelial markers.
- Low TIP60 levels correlate with poor survival in breast cancer patients.
Conclusions:
- TIP60 functions as a suppressor of breast cancer cell migration and metastasis.
- TIP60 regulates EMT via the DNMT1/SNAIL2 axis.
- TIP60 downregulation is associated with poor prognosis in breast cancer patients.
- TIP60 levels may serve as a prognostic marker, and TIP60 stabilization is a potential therapeutic strategy.
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