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.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Metastasis, a leading cause of poor prognosis in patients with cancer, accounts for 90% of all cancer-related deaths
Considering the fact that diacetylated TWIST1 induced by TIP60 recruits bromodomain-containing protein 4 (BRD4) which is associated with acetylated H3 and H4 histones, as well as P-TEFb of the RNA-polymerase II (Pol II) elongation complex at the promoter and enhancer regions of target genes such as WNT5A [18], we investigated the mechanisms underlying the formation of the Spermatogenic Zip 1 (SPZ1)–TWIST1 complex
Acetylation of SPZ1 induced by TIP60 leads to the formation of the SPZ1–TWIST1 complex and its nuclear translocation, which activates vascular endothelial growth factor (VEGF) expression in hepatoma cells
Summary
Despite the identification of potential oncogenic drivers and their roles as master regulators of cancer initiation, the mechanisms underlying tumorigenesis and metastasis. 10 Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan. TWIST1, a basic helix-loop-helix (bHLH) transcription factor, was originally identified as a mesoderm-inducing factor in Drosophila [3] and is known as a major inducer of EMT in human mammary epithelial cells [4] and other cancers such as sarcoma, melanoma, and lymphoma [4, 5]. Increased TWIST1 expression promotes EMT by regulating cell motility and invasive activity and enhances some features of cancer stem cells through control of downstream gene expression [5, 6]. The molecular pathways through which TWIST1 and the downstream events are regulated during tumor metastasis have not been well characterized [4]
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