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Yes tyrosine kinase signaling promotes liver cancer development [DSP294_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: GSE179750 | GEO | 2022/01/05

REPOSITORIES: GEO

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Yes tyrosine kinase signaling promotes liver cancer development [DSP294_SNU449]

Project description: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.

2022-01-05 | GSE179751 | GEO

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CRKL enhances YAP signaling through binding and JNK/JUN pathway activation in liver cancer

Project description:Hepatocellular carcinoma (HCC) presents a major health issue due to its rising incidence and limited therapeutic options. The Hippo pathway transducers yes-associated protein (YAP) and WW-domain containing transcription regulator 1 (WWTR1/TAZ) are key regulators of liver tu-morigenesis promoting tumor formation and progression. Although first inhibitors are in clinical trials, targeting the upstream activation of YAP/TAZ could prove equally beneficial. To identify regulators of YAP/TAZ activity, we carried out a proximity labelling approach (BioID) coupled to mass-spectrometry. We verified CRKL as a new YAP-exclusive interaction partner, which is overexpressed in HCC patients correlating with YAP expression and activity as well as poor survival prognosis. In vitro experiments demonstrated CRKL dependent cell survival and loss of YAP binding induced through actin disruption. Moreover, we delineated an activation of the JNK/JUN pathway by CRKL, which promoted YAP transcription. Our data thus illustrated that CRKL not only promoted YAP activity through its binding but also through the induction of YAP transcription by JNK/JUN activation. This highlights the JNK/JUN pathway as a possible target to abrogate YAP expression in HCC patients.

2024-11-26 | PXD058235 | Pride

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SDHA/B reduction promotes hepatocellular carcinoma proliferation by removing cullin1 NEDDylation and stabilizing YAP/TAZ

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2012-11-01 | E-GEOD-35004 | biostudies-arrayexpress

Syngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma.

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