Abstract
Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells. Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms. The involvement of microRNA in cancer progression has recently been reported, though whether they have a role in activating YAP and TAZ in human cancer cells remains unclear. Here, we report a microRNA, miR-129-5p, directly represses YAP and TAZ expression, leading to the inactivation of TEA domain (TEAD) transcription, and the downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A. Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival. Hence, we demonstrate a novel mechanism for YAP and TAZ activation in cancers, indicating not only a potentially pivotal role for miR-129-5p in the progression of ovarian cancer, but also offering new therapeutic strategies to circumvent the disease.
Highlights
Ovarian cancer is the most lethal gynecological cancer and the fifth leading cause of cancer-related death in women [1, 2]
To investigate the role microRNAs may play in regulating Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) expression, we applied publicly available algorithms from TargetScan to reveal that YAP and TAZ might be potential targets of miR-129-5p (Figure 1A)
Our western blot analysis revealed that expression levels of YAP and TAZ were significantly decreased in miR-1295p-transfected cells, but increased in miR-129-5p-silenced cells (Figure 1B and Supplementary Figure 1A–1B), suggesting that miR-129-5p negatively regulates these two proteins
Summary
Ovarian cancer is the most lethal gynecological cancer and the fifth leading cause of cancer-related death in women [1, 2]. Despite enormous improvements in surgical techniques and therapeutic strategies, the prognosis for patients with ovarian cancer remains dismal, largely attributed to the rapid and uncontrolled tumor growth and insensitivities to chemotherapy [3, 4]. A better understanding of the mechanisms contributing to ovarian cell proliferation and anti-apoptosis may allow the identification of novel targets for therapeutic intervention. The Hippo pathway represents a novel tumorsuppressor pathway and is considered to be a key regulator of tumor cell proliferation and survival [7]. TEAD activation promotes the transcription of genes, such as connective tissue growth factor (CTGF) and Cyclin A, leading to the promotion of cell proliferation and survival [15,16,17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
