Tissue inhibitor of metalloproteinase-1 (TIMP-1), a member of the TIMP family (TIMP-1 to 4), is highly expressed in various types of cancer and forms a complex with its receptor CD63 and Integrin β1. However, the precise oncogenic mechanism of TIMP-1 remains unclear. Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) are transcription co-activators enhancing the transcription of specific genes related to cell proliferation. But the mechanism of aberrant YAP/TAZ activation in cancer is not fully understood. Here, we showed that TIMP-1 activates YAP/TAZ as novel downstream targets to promote cell proliferation. The TIMP-1-CD63-Integrin β1 axis activates Src and promotes RhoA-mediated F-actin assembly, leading to LATS1/2 inactivation. This results in under-phosphorylation, protein stabilization and nuclear translocation of YAP/TAZ (YAP/TAZ activation); CTGF production; and cell proliferation. Furthermore, the TIMP-1-YAP/TAZ axis is aberrantly activated in various types of cancer cells or tissues. TIMP-1 knockdown inhibits cell proliferation through YAP/TAZ inactivation in cancer cells. This study found that TIMP-1 accelerates cell proliferation through YAP/TAZ activation in cancer, and suggests the TIMP-1-YAP/TAZ axis may be a novel potential drug target for cancer patients.
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We thank Professor Koichiro Ozawa (Department of Pharmacotherapy, Hiroshima University) for valuable discussion and Professor Makiko Fujii (Department of Global Dental Medicine and Molecular Oncology, Hiroshima University) for providing us HA-tagged YAP-WT vector and anti-HA antibody. This work was funded, in part, by JSPS KAKENHI Grant Number JP25293373 and JP16H05503 to (TT) and 17K17084 to (TA). Hanako Umehara currently belongs to department of advanced prosthodontics, Hiroshima University.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Ando, T., Charindra, D., Shrestha, M. et al. Tissue inhibitor of metalloproteinase-1 promotes cell proliferation through YAP/TAZ activation in cancer. Oncogene 37, 263–270 (2018). https://doi.org/10.1038/onc.2017.321
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