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.

Details

Title
TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial–mesenchymal transition and metastasis in liver cancer
Author
Li-Ting, Wang 1 ; Shen-Nien, Wang 2 ; Shyh-Shin Chiou 3 ; Kwei-Yan Liu 1 ; Chee-Yin, Chai 4 ; Cheng-Ming, Chiang 5 ; Huang, Shau-Ku 6 ; Yokoyama, Kazunari K 7   VIAFID ORCID Logo  ; Shih-Hsien Hsu 8 

1  Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan 
2  Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Pingtung Hospital, Ministry of Health and Welfare, Pingtung 900, Taiwan 
3  Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Division of Hematology-Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan 
4  Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan 
5  Simmons Comprehensive Cancer Center, Departments of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA 
6  Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 115, Zhunan, Taiwan 
7  Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Center of Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan 
8  Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan 
Pages
518-532
Publication year
2019
Publication date
Jan 2019
Publisher
Nature Publishing Group
ISSN
09509232
e-ISSN
14765594
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41388-018-0457-z
ProQuest document ID
2170926124
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.