Repression of YAP by NCTD disrupts NSCLC progression

Abstract

The efficacy of available lung cancer therapeutic interference is significantly limited by various resistance mechanisms to those drugs. Activation of the oncogene YAP underlying the initiation, progression, and metastasis of lung cancer associates with poor prognosis and confers drug resistance against targeted therapy. In this study, we evaluated the specificity of norcantharidin (NCTD) in repressing YAP to inhibit non-small cell lung carcinoma (NSCLC) progression. Our study revealed that YAP signal pathways were aberrantly activated in lung cancer tissues and cells which rendered more proliferative and invasive phenotypes to human lung cancer cells. We confirmed that NCTD specifically repressed YAP signaling pathway to interfere the YAP-mediated non-small cell lung carcinoma progression and metastasis via arresting cell cycle, enhancing apoptosis and inducing senescence. We also found NCTD-mediated repression of YAP decreased epithelial-to-mesenchymal transition (EMT) and reduced the motile and invasive cellular phenotype in vitro via enhancing E-cadherin and decreasing fibronectin/vimentin. Mechanistic investigations revealed that NCTD transcriptionally downregulated YAP and post-translationally modulated the subcellular redistribution of YAP between nucleus and cytoplasm. Collectively, our results indicated that NCTD is a novel therapeutic drug candidate for NSCLC which specifically and sensitively target YAP signal pathway.

EMT induced by loss of LKB1 promotes migration and invasion of liver cancer cells through ZEB1‑induced YAP signaling

“…YAP is a well-studied oncogene in the liver that drives liver enlargement as well as liver tumor formation; a previous study revealing that ectopic expression of YAP resulted in accelerated liver tumor progression ( 14 ). In addition, depletion of YAP attenuates the metastasis potential of cells ( 27 ). The results of the present study demonstrated that YAP activation promotes liver cancer progression.…”

Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer

“…Resistance to 5‐FU in CRC is a major clinical problem. While there are a number of mechanisms reported to be responsible for drug resistance, activation of several tissue polarity regulation pathways is quite appealing . Like wnt, notch, and hedgehog signaling pathways, YAP1 is an important regulator for embryonic development, organ size, cell differentiation, and cancer development .…”

Dual roles of yes-associated protein (YAP) in colorectal cancer

“…YAP was originally identified by its association with the YES Src tyrosine kinase and has been shown to be a transcription factor whose cytoplasmic/nuclear shuttling is controlled by post-translational phosphorylation events [ 34 , 35 ]. As the gene locus of YAP is frequently amplified in various human cancers [ 25 , 36 , 37 ], the elevated expression of YAP has been consistently observed in multiple types of human cancers, for example non-small-cell lung cancer (NSCLC) [ 38 , 39 ], gastric cancer [ 40 , 41 ], urothelial carcinoma of the bladder (UCB) [ 42 , 43 ], esophageal squamous cell carcinoma (ESCC) [ 44 , 45 ], ovarian cancer [ 46 , 47 ], CRC [ 48 , 49 ], and cervical cancer [ 50 , 51 ].…”

“…Overexpression of nuclear YAP has been observed in multiple types of human cancers [ 38 – 51 ] and is significantly associated with worse overall survival [ 46 , 169 – 171 ]. In our previous study, Sun et al [ 172 ] showed through meta-analysis of 21 studies that YAP overexpression was closely associated with adverse effects on overall survival (OS) and disease free survival (DFS) in numerous cancers.…”