Enhanced PAPSS2/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis

• DOI: 10.1038/s41418-018-0147-y
• Publication Date: 2018-06-28T09:59:27Z
• Authors: Yihong Zhang; Xiuqun Zou; Wenli Qian; Xiaoling Weng; Lin Zhang; Liang Zhang; Shuang Wang; Xuan Cao; Li Ma; Gang Wei; Yingjie Wu; Zhaoyuan Hou
• Keywords: Mice, Inbred BALB C; 0303 health sciences; Sulfates; Mice, Nude; Breast Neoplasms; Sulfate Adenylyltransferase; 3. Good health; Mice; 03 medical and health sciences; HEK293 Cells; Versicans; Cell Movement; Multienzyme Complexes; Cell Line, Tumor; MCF-7 Cells; Animals; Heterografts; Humans; Female; Snail Family Transcription Factors; Neoplasm Metastasis; Cell Proliferation; Signal Transduction

The zinc finger protein Snail is a master regulator of epithelial-mesenchymal transition (EMT) and a strong inducer of tumor metastasis, yet the signal cascades triggered by Snail have not been completely revealed. Here, we report the discovery of the sulfation program that can be induced by Snail in breast cancer cells, and which plays an essential role in cell migration and metastasis. Specifically, Snail induces the expression of PAPSS2, a gene that encodes a rate-limiting enzyme in sulfation pathway, and VCAN, a gene that encodes the chondroitin sulfate proteoglycan Versican in multiple breast cancer cells. Depletion of PAPSS2 in MCF7 and MDA-MB-231 cells results in reduced cell migration, while overexpression of PAPSS2 promotes cell migration. Moreover, MDA-MB-231-shPAPSS2 cells display a significantly lower rate of lung metastasis and lower number of micrometastatic nodules in nude mice, and conversely, MDA-MB-231-PAPSS2 cells increase lung metastasis. Similarly, depletion of VCAN dampens the cell migration activity induced by Snail or PAPSS2 in MCF 10A cells. Moreover, PAPSS inhibitor sodium chlorate effectively decreases cell migration induced by Snail and PAPSS2. More importantly, the expression of Snail, PAPSS2, and VCAN is positively correlated in breast cancer tissues. Together, these findings are important for understanding the genetic programs that control tumor metastasis and may identify previously undetected therapeutic targets to treat metastatic disease.