A novel role for microRNA-129-5p in inhibiting ovarian cancer cell proliferation and survival via direct suppression of transcriptional co-activators YAP and TAZ

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.

MicroRNA-129 in Human Cancers: from Tumorigenesis to Clinical Treatment

“…Tan et al demonstrated that downregulation of miR-129-5p highly correlated with ovarian cancer progression with poor prognosis [49]. This finding also uncovered a novel mechanism for YAP/TAZ overexpression, and may suggest new targets for clinical intervention in human cancers.…”

“…Later on, Xiao et al speculated that DNA methylation alters the expression of miR-129 in lung cancer and miR-129 was conferred the tumour suppressive potential [48]. Tan et al reported that the promoter region of miR-129-5p could be potentially targeted by p53, whose malfunction was frequently detected in human cancers [49]. Meanwhile, multi-CpG-rich loci of TRPM3 promoter were retrieved by the UCSC genome browser, recommending that miR-129-5p downregulation might be associated with genomic methylation.…”

“…Glioma cell proliferation was impaired with inhibition of the NTSR1 function or the upregulation of miR-129-3p [58]. One study by Tan et al indicated that miR-129-5p directly repressed YAP and TAZ expression, inactivated TEA domain (TEAD) and led to the subsequent inhibition of ovarian cancer cell proliferation, survival and tumorigenicity [49]. Interestingly, miR-129-5p was found to be involved in downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A, suppressing the growth of LSCC by targeting APC [30].…”

“…NTS/NTSR1 could regulate a broad range of normal physiological processes, and as a down-stream regulator of the NTS/ NTSR1/c-Myc/miRNA/CDK axis, miR-129 might be a more ideal target with particular effects for glioblastoma therapy [58]. Understanding the particular role of miR-129-5p in the pathogenesis of ovarian cancer and activation of the YAP/TAZ signaling pathway promised to spread our knowledge of the biological basis of cancer development, and may also allow the improvement of new therapeutic strategies against ovarian cancer [49]. It was reported that miR-129-5p was down-regulated and could repress RET directly in MTC cells.…”

Downregulation of miR-129-2 by promoter hypermethylation regulates breast cancer cell proliferation and apoptosis

“…Dual functions for miR-129, as a tumor suppressor and oncogene, have been observed in different types of cancers. It has been reported that miR-129-5p is downregulated in neuroendocrine tumors, gastric cancer, ovarian cancer and medullary thyroid carcinoma and plays a tumor-suppressor role in these tumors (22,(26)(27)(28). Epigenetic regulation of miR-129-2 was reported in glioma and lung cancer (8,9).…”