miR-550a-3-5p acts as a tumor suppressor and reverses BRAF inhibitor resistance through the direct targeting of YAP

Abstract

Although evidence has emerged to suggest that YAP overexpression is a crucial factor for tumor progression and resistance to targeted drugs in multiple cancers, the miRNA-mediated YAP regulation is still unclear. Here we show that the novel miR-550a-3-5p acts as a tumor suppressor and reverses BRAF inhibitor resistance through the direct targeting of YAP. Our data showed that the miR-550a-3-5p suppressed cell proliferation, metastasis, and tumor sphere formation through the direct inhibition of YAP and its oncogenic pathway in various cancer cell types. In addition, we showed that the YAP signature was associated with poor survival of colon cancer and identified an inverse correlation between miR-550a-3-5p and YAP in colon cancer tissues. Interestingly, this inverse correlation was regulated in a density-dependent manner. Furthermore, high levels of miR-550a-3-5p were associated with a good prognosis of esophageal cancer, which was suggestive of the clinical relevance of miR-550a-3-5p-mediated YAP regulation in multiple cancers. Importantly, we demonstrated that miR-550a-3-5p treatment sensitized vemurafenib-resistant colon and melanoma cells through YAP inhibition with reduced AKT activity. Moreover, the tumor-suppressive activity of miR-550a-3-5p and its sensitization effect for vemurafenib resistance were also observed in tumor xenograft models. Collectively, our data suggest that miR-550a-3-5p acts as a tumor suppressor through the targeting of oncogenic YAP and may be a new therapeutic tool for YAP-mediated BRAF inhibitor resistance in BRAF-mutant cancer cells.