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

Oncogene
Li-Ting WangShih-Hsien Hsu

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.

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Citations

Dec 31, 2019·Oxidative Medicine and Cellular Longevity·Ekaterina BayurovaMaria Isaguliants
May 8, 2019·Biological & Pharmaceutical Bulletin·Xianmin WangWanli Deng
Dec 25, 2019·Signal Transduction and Targeted Therapy·Yuan ChengXiawei Wei
Dec 22, 2020·Frontiers in Pharmacology·Bo DongYadi Wu
Dec 17, 2020·Signal Transduction and Targeted Therapy·Yuan ChengXiawei Wei
Apr 12, 2021·Environmental Science and Pollution Research International·Yujian SangXianqing Zhou

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Methods Mentioned

BETA
acetylates
co-immunoprecipitation
electrophoresis
immunoprecipitation
fluorescence resonance energy transfer
FRET
fluorescence imaging
xenografts
acetylation
nuclear

Software Mentioned

Living Image

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