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

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.

Ursolic Acid Inhibits Tumor Growth <i>via</i> Epithelial-to-Mesenchymal Transition in Colorectal Cancer Cells

“…25) EMT promotes migration by downregulating E-cadherin and up-regulating transcription factors such as TWIST, Snail and Integrin. [26][27][28] Liu et al found that the Chinese medicinal herbal preparation Jianpijiedu (JPJD) inhibits TGF-β/Smad activity, stabilizes Snail, and up-regulates E-cadherin, thereby inhibiting EMT, tumor invasion, and metastasis. 29) Curcumin, which is derived from the rhizome of turmeric (Curcuma longa), prevents EMT progression in intestinal fibrosis.…”

BRD4 Promotes Gastric Cancer Progression and Metastasis through Acetylation-Dependent Stabilization of Snail

“…Specifically, we demonstrated that BRD4 is not only required for gastric cancer cell proliferation, but also essential for invasion and metastasis in vitro and in vivo. A role of BRD4 in cancer metastasis was recently implicated in the zinc finger MYND-type containing 8 (ZMYND8)-mediated control of HIF transcriptional activity (28) and Spermatogenic Zip 1 (SPZ1)-Twist1 complex-mediated cancer cell metastasis (29). BRD4 is a promising anticancer target as revealed by several loss-of-function genetic screens, and there are significant interests in development BET inhibitors for cancer therapy (30)(31)(32)(33)(34)(35).…”

HIV-1 Reverse Transcriptase Promotes Tumor Growth and Metastasis Formation via ROS-Dependent Upregulation of Twist

“…Recent study has shown that ROS induce EMT by activating Snail expression, which then represses the expression of E-cadherin, a classical marker of the epithelial phenotype [100]. Several independent studies demonstrated that EMT can be induced by direct contact of epithelial cells with HIV proteins [24, 86, 101, 102]. To see if this is the case for 4T1luc2 cells expressing RT, we monitored them for the expression of E-cadherin , mesenchymal cell phenotype markers N-cadherin and Vimentin , and of two transcription factors, heavily involved in EMT, Twist and Snail [71, 98].…”