ABSTRACT
Activation of metastatic reprogramming is critical for tumour metastasis. However, more detailed knowledge of the underlying mechanism is needed to enable targeted intervention. Here, we show that paraspeckle component 1 (PSPC1), identified in an aberrant 13q12.11 locus, is upregulated and associated with poor survival in patients with cancer. PSPC1 promotes tumorigenesis, epithelial-to-mesenchymal transition (EMT), stemness and metastasis in multiple cell types and in spontaneous mouse cancer models. PSPC1 is the master activator for transcription factors of EMT and stemness and accompanies c-Myc activation to facilitate tumour growth. PSPC1 increases transforming growth factor-ß1 (TGF-ß1) secretion through an interaction with phosphorylated and nuclear Smad2/3 to potentiate TGF-ß1 autocrine signalling. Moreover, PSPC1 acts as a contextual determinant of the TGF-ß1 pro-metastatic switch to alter Smad2/3 binding preference from tumour-suppressor to pro-metastatic genes. Having validated the PSPC1-Smads-TGF-ß1 axis in various cancers, we conclude that PSPC1 is a master activator of pro-metastatic switches and a potential target for anti-metastasis drugs.
Subject(s)
Autocrine Communication , Cell Movement , Epithelial-Mesenchymal Transition , Neoplasms/metabolism , Neoplastic Stem Cells/metabolism , Nuclear Proteins/metabolism , RNA-Binding Proteins/metabolism , Signal Transduction , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Transforming Growth Factor beta1/metabolism , A549 Cells , Animals , Female , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Male , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Neoplasm Metastasis , Neoplasms/genetics , Neoplasms/pathology , Neoplastic Stem Cells/pathology , Nuclear Proteins/genetics , PC-3 Cells , Phenotype , Phosphorylation , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , RNA-Binding Proteins/genetics , Smad2 Protein/genetics , Smad3 Protein/genetics , Time Factors , Transforming Growth Factor beta1/geneticsABSTRACT
Breast cancer is the most universal cancer in women, but the medications for breast cancer usually cause serious side effects and offer no effective treatment for triple-negative breast cancer. Here, we investigated the growth inhibitory effects of gallic acid (GA), (-)-epigallocatechin gallate (EGCG), or 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (5GG) combined with quercetin (Que) on breast cancer cells. In this study, we tested the combined effects of these compounds on estrogen receptor (ER)/human epidermal growth factor 2 (Her2)-negative (MDA-MB-231), ER-positive/Her2-negative (BT483), and ER-negative/Her2-positive (AU565) breast cancer cells. After treatment of each cell line with these compounds, we found that Que combined with 5GG induced S-phase arrest and apoptosis in MDA-BM-231 cells through downregulation of S-phase kinase protein 2 expression, but induced G2/M-phase arrest and apoptosis in AU565 cells through downregulation of Her2 expression. Additionally, Que combined with 5GG was more effective in inhibiting MDA-MB-231 cell growth than Que combined with EGCG (5GG analogue) or GA. The combination of 5GG and Que can offer great potential for the chemoprevention of ER-negative breast cancer.
