A novel role for the SUMO E3 ligase PIAS1 in cancer metastasis.

Shorafidinkhuja Dadakhujaev,Carolina Salazar-Arcila,Amrita Singh Chandhoke,Frank R Jirik,Arvind Kumar Singla,Stuart J Netherton,Shirin Bonni

doi:10.18632/oncoscience.27

Shorafidinkhuja Dadakhujaev, Carolina Salazar-Arcila + Show 5 more

Open Access

https://doi.org/10.18632/oncoscience.27

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Journal: Oncoscience	Publication Date: Mar 31, 2014
Citations: 30	License type: cc-by

Affiliation: University of Calgary

Abstract

Tumor metastasis contributes to the grave morbidity and mortality of cancer, but the mechanisms underlying tumor cell invasiveness and metastasis remain incompletely understood. Here, we report that expression of the SUMO E3 ligase PIAS1 suppresses TGFβ-induced activation of the matrix metalloproteinase MMP2 in human breast cancer cells. We also find that knockdown of endogenous PIAS1 or inhibition of its SUMO E3 ligase activity stimulates the ability of TGFβ to induce an aggressive phenotype in three-dimensional breast cancer cell organoids. Importantly, inhibition of the SUMO E3-ligase activity of PIAS1 in breast cancer cells promotes metastases in mice in vivo. Collectively, our findings define a novel and critical role for the SUMO E3 ligase PIAS1 in the regulation of the invasive and metastatic potential of malignant breast cancer cells. These findings advance our understanding of cancer invasiveness and metastasis with potential implications for the development of biomarkers and therapies in breast cancer.

Highlights

Tumor cell invasiveness and metastasis pose a major obstacle in the treatment of cancer [1,2,3]
Expression of a SUMO E3 ligase inactive mutant of PIAS1, owing to replacement of Cysteine 350 with serine (PIAS1 (CS)), enhanced transforming growth factor β (TGFβ)-induced activation of matrix metalloproteinase 2 (MMP2) in MDA-MB-231 breast cancer cells (Figure 1A) [18, 26]. These results suggest that the SUMO E3 ligase PIAS1 regulates TGFβ-induced MMP2 activation in breast cancer cells
We have discovered that the SUMO E3 ligase PIAS1 is a critical regulator of breast cancer invasion and metastasis

Summary

Introduction

Tumor cell invasiveness and metastasis pose a major obstacle in the treatment of cancer [1,2,3]. Epithelial mesenchymal transition (EMT) represents a fundamental cellular process that is thought to contribute to epithelial tumor cell invasiveness and metastasis [5,6,7,8]. Determining the role of regulators of EMT in the control of the malignant features of epithelial tumors including their invasiveness and metastasis represents a worthwhile strategy in gaining novel insights in cancer biology. EMT comprises the loss of apical-basal polarity and of cell-cell adhesions resulting from the downregulation or mislocalization of epithelial markers such as E-cadherin and the expression of mesenchymal proteins such as N-cadherin [6, 7]. A critical functional outcome of EMT is the increased motility of cells, which may provide a basis for the significance of EMT in cancer cell behavior [9, 10]

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