TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial–mesenchymal transition and metastasis in liver cancer

Li Ting Wang, Shen Nien Wang, Shyh Shin Chiou, Kwei Yan Liu, Chee Yin Chai, Cheng Ming Chiang, Shau Ku Huang, Kazunari K. Yokoyama, Shih Hsien Hsu

Research output: Contribution to journalArticle

Abstract

Metastasis is the main cause of cancer mortality. However, the triggering mechanisms and regulation of epithelial–mesenchymal transition (EMT) factors in the commitment of metastasis have not been well characterized. Spermatogenic Zip 1 (SPZ1) acts as a proto-oncogene and an upstream regulator of EMT during tumorigenesis. Here we report that the HIV-1 Tat-interacting protein 60 kDa (Tip60) acetyltransferase mediates acetylation at lysine residues of SPZ1 at positions 369 and 374, and of TWIST1 at positions 73 and 76, which are required for SPZ1–TWIST1 complex formation and cancer cell migration in vitro and in vivo. Ectopic SPZ1 and TWIST1 expression, but not that of TWIST1 alone, enhanced vascular endothelial growth factor (VEGF) expression via the recruitment of bromodomain-containing protein 4 (BRD4), thus enhancing RNA-Pol II-dependent transcription and inducing metastasis. Neutralization of VEGF using humanized monoclonal antibodies such as Avastin, effectively abrogated the EMT and oncogenesis induced by the acetylated SPZ1–TWIST1 complex. Our findings highlight the importance of acetylation signaling in the SPZ1–TWIST1–BRD4 axis in the mediation of EMT and its regulation during tumor initiation and metastasis.

Original languageEnglish (US)
JournalOncogene
DOIs
Publication statusAccepted/In press - Jan 1 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Wang, L. T., Wang, S. N., Chiou, S. S., Liu, K. Y., Chai, C. Y., Chiang, C. M., ... Hsu, S. H. (Accepted/In press). TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial–mesenchymal transition and metastasis in liver cancer. Oncogene. https://doi.org/10.1038/s41388-018-0457-z