Dataset Information

Yes tyrosine kinase signaling promotes liver cancer development [DSP244_262_SNU387]

ABSTRACT: Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179749 | GEO | 2022/01/05

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.

Dataset Information

Yes tyrosine kinase signaling promotes liver cancer development [DSP244_262_SNU387]

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure