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- Title
Signaling by the tyrosine kinase Yes promotes liver cancer development.
- Authors
Guégan, Jean-Philippe; Lapouge, Marjorie; Voisin, Laure; Saba-El-Leil, Marc K.; Tanguay, Pierre-Luc; Lévesque, Kim; Brégeon, Jérémy; Mes-Masson, Anne-Marie; Lamarre, Daniel; Haibe-Kains, Benjamin; Trinh, Vincent Q.; Soucy, Geneviève; Bilodeau, Marc; Meloche, Sylvain
- Abstract
Most patients with hepatocellular carcinoma (HCC) are diagnosed at a late stage and have few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or a dominant oncogene that can be targeted pharmacologically, unlike in other cancer types. Here, we report the identification of a previously uncharacterized oncogenic signaling pathway in HCC that is mediated by the tyrosine kinase Yes. Using genetic and pharmacological interventions in cellular and mouse models of HCC, we showed that Yes activity was necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes was sufficient to induce liver tumorigenesis. Yes phosphorylated the transcriptional coactivators YAP and TAZ (YAP/TAZ), promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors. We also showed that YAP/TAZ were effectors of the Yes-dependent oncogenic transformation of hepatocytes. Src family kinase activation correlated with the tyrosine phosphorylation and nuclear localization of YAP in human HCC and was associated with increased tumor burden in mice. Specifically, high Yes activity predicted shorter overall survival in patients with HCC. Thus, our findings identify Yes as a potential therapeutic target in HCC. A Yes to new therapies?: Patients with hepatocellular carcinoma (HCC) have few therapeutic options and often face a poor prognosis. Genetic profiling of tumors has enabled the classification of different HCC subclasses but has not yet identified clear driver oncogenes to target. The transcriptional coactivators YAP/TAZ are implicated in HCC development, although mutations in their genes are not associated with disease. Guégan et al. showed that the activity of the tyrosine kinase Yes upstream of YAP/TAZ promoted HCC cell proliferation in vitro and tumor development in vivo in a manner dependent on the phosphorylation and nuclear translocation of YAP/TAZ. Data from patients with HCC showed that increased Yes activity, rather than mutations in Yes or increased Yes abundance, correlated with poor survival, suggesting that Yes may be a therapeutic target to treat HCC.
- Subjects
LIVER cancer; KINASES; CARCINOGENESIS; YAP signaling proteins; GENETIC engineering; PROTEIN-tyrosine kinases; LIVER tumors
- Publication
Science Signaling, 2022, Vol 15, Issue 717, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abj4743