Research Papers:

Oncostatin M suppresses metastasis of lung adenocarcinoma by inhibiting SLUG expression through coordination of STATs and PIASs signalings

Chih-Ming Pan, Mong-Lien Wang, Shih-Hwa Chiou, Hsiao-Yun Chen and Cheng-Wen Wu _

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Oncotarget. 2016; 7:60395-60406. https://doi.org/10.18632/oncotarget.10939

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Chih-Ming Pan1, Mong-Lien Wang1, Shih-Hwa Chiou2,4, Hsiao-Yun Chen3, Cheng-Wen Wu1,3,5

1Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

2Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan

3Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

4Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan

5Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan

Correspondence to:

Cheng-Wen Wu, email: cwwu@ym.edu.tw

Keywords: oncostatin M, SLUG, STAT1, PIAS4, metastasis

Received: May 13, 2016     Accepted: July 19, 2016     Published: July 29, 2016


Oncostatin M (OSM) is linked with multiple biological responses including growth and differentiation. Previous reports showed inhibitory effects of OSM in tumor progression while others showed promoting effects. The dual role of OSM in the development of various cancers is still unclear. We previously described OSM-mediated SLUG suppression, leading to repressed metastasis of lung adenocarcinoma (LAC) cells. However, the underlying mechanism remains elusive. Here, we showed that OSM suppresses SLUG express in LAC cells through a STAT1-dependent transcriptional inhibition. Knockdown of STAT1 reversed the OSM-suppressed SLUG expression and rescued the OSM-mediated inhibition of cell proliferation, migration, and invasion in vitro, as well as pulmonary metastasis in vivo. STAT1 suppressed SLUG transcription through binding to its promoter region in response to OSM. Furthermore, PIAS4, a co-repressor of STAT, and HDAC1 were able to bind to STAT1 on SLUG promoter region, resulting in reduced H3K9 acetylation and suppressed SLUG expression upon OSM treatment. In contrast, PIAS3 bound to activated STAT3, another effector of OSM, in response to OSM and blocked the binding of STAT3 to SLUG promoter region, preventing STAT3-dependent activation of SLUG transcription. Our findings suggested that OSM suppresses SLUG expression and tumor metastasis of LAC through inducing the inhibitory effect of the STAT1-dependent pathway and suppressing the activating effect of STAT3-dependent signaling. These results can serve as a scientific basis for the potential therapeutic intervention of OSM in cancer cells.

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