MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis

• Published in: The EMBO journal Vol. 31; no. 2; pp. 481 - 493
• Main Authors: Hosono, Yasuyuki, Yamaguchi, Tomoya, Mizutani, Eri, Yanagisawa, Kiyoshi, Arima, Chinatsu, Tomida, Shuta, Shimada, Yukako, Hiraoka, Michiyo, Kato, Seiichi, Yokoi, Kohei, Suzuki, Motoshi, Takahashi, Takashi
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 18.01.2012; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: actomyosin; Actomyosin - metabolism; Adenocarcinoma - pathology; Animals; Cell adhesion & migration; Cell Line; Cell Line, Tumor; Cell Movement - physiology; Cell Shape; Cellular biology; CpG Islands - genetics; Cytoskeletal Proteins - physiology; Cytoskeleton; DNA Methylation; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - physiology; Dogs; Gene Expression Regulation, Neoplastic; Humans; Kidney; Lung cancer; Lung Neoplasms - pathology; Metastasis; Myosin Light Chains - metabolism; Neoplasm Invasiveness; Neoplasm Metastasis - physiopathology; Phosphorylation; Promoter Regions, Genetic - genetics; Protein Processing, Post-Translational; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - physiology; ROCK1; Transcription Factors; Transcriptional Activation
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.416

Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of myosin binding protein H (MYBPH) as a transcriptional target of TTF‐1 (also known as NKX2‐1 and TITF1), a master regulator of lung development that also plays a role as a lineage‐survival oncogene in lung adenocarcinoma development. MYBPH inhibited assembly competence‐conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK), unexpectedly through its direct physical interaction with Rho kinase 1 (ROCK1) rather than with RLC. Consequently, MYBPH inhibited ROCK1 and negatively regulated actomyosin organization, which in turn reduced single cell motility and increased collective cell migration, resulting in decreased cancer invasion and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of TTF‐1‐positive lung adenocarcinomas, which appears to be in accordance with its deleterious functions in lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of TTF‐1 expression with favourable prognosis in lung adenocarcinoma patients. The TTF‐1 transcription factor is upregulated in lung adenocarcinomas, where it apparently suppresses malignant progression. One of its targets, MYBPH, inhibits Rho kinase 1 and hence cell motility and invasion, providing a potential explanation for the protective function of TTF‐1.