MEST induces Twist-1-mediated EMT through STAT3 activation in breast cancers

• Published in: Cell death and differentiation Vol. 26; no. 12; pp. 2594 - 2606
• Main Authors: Kim, Min Soo, Lee, Hyun Sook, Kim, Yun Jae, Lee, Do Yup, Kang, Sung Gyun, Jin, Wook
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2019; Nature Publishing Group UK
• Subjects: Animals; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement - physiology; Cells, Cultured; Epithelial-Mesenchymal Transition; Female; Humans; Interleukin 6; Janus kinase 2; MCF-7 Cells; Metastases; Metastasis; Mice; Neoplasm Metastasis; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear transport; Proteins - genetics; Proteins - metabolism; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumorigenicity; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism; Up-Regulation
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-019-0322-9

The loss of imprinting of MEST has been linked to certain types of cancer by promoter switching. However, MEST-mediated regulation of tumorigenicity and metastasis are yet to be understood. Herein, we reported that MEST is a key regulator of IL-6/JAK/STAT3/Twist-1 signal pathway-mediated tumor metastasis. Enhanced MEST expression is significantly associated with pathogenesis of breast cancer patients. Also, MEST induces metastatic potential of breast cancer through induction of the EMT-TFs-mediated EMT program. Moreover, MEST leads to Twist-1 induction by STAT3 activation and subsequently enables the induction of activation of the EMT program via the induction of STAT3 nuclear translocation. Furthermore, the c-terminal region of MEST was essential for STAT3 activation via the induction of JAK2/STAT3 complex formation. Finally, MEST is required for metastasis in an experimental metastasis model. These observations suggest that MEST is a promising target for intervention to prevent tumor metastasis.