Signaling by the tyrosine kinase Yes promotes liver cancer development

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.

The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in colon cancer cells

“…Besides the canonical Hippo signaling pathway, the nucleo-cytoplasmic shuttling of YAP and TAZ is under the control of many other inputs. In particular, YAP and TAZ retention in the nucleus is promoted by the action of different tyrosine kinases, such as ABL or SFKs (Src Family Kinases) which phosphorylate the C-termini of YAP and TAZ (Y357 or Y316 respectively; Byun et al, 2017; Ege et al, 2018; Guégan et al, 2022; Kedan et al, 2018; Lamar et al, 2019; Li et al, 2016). Due to its high relevance for colon cancer, we focused our analysis on SRC, frequently activated in colon carcinoma (Sirvent et al, 2020).…”

YES, a novel therapeutic target in hepatocellular carcinoma

“…These findings identify YES as an oncogenic driver in liver cancer. 4 To evaluate the cell-autonomous role of YES in sustaining the proliferation of HCC cells in vivo , we engineered HCC cells with an inducible YES1 shRNA and transplanted the cells in immunodeficient mice. Hepatocyte-specific depletion of YES completely abolished HCC growth, associated with a reduction in cell proliferation and increased apoptosis.…”

“…We showed that high YES activity, rather than YES1 mutation or increased YES abundance, predicts shorter overall survival in HCC patients, underscoring the translational relevance of our findings. 4 …”

“…As an approach to identify novel protein kinases controlling liver cancer cell proliferation, we performed an unbiased loss-of-function shRNA screen of the human kinome in HCC cells and identified the SRC-family kinase (SFK) YES as the top-scoring hit. 4 SFKs are a family of non-receptor tyrosine kinases that play a key role in transducing signals from multiple receptors to regulate cell proliferation, differentiation, survival, cytoskeleton dynamics, and motility. 5 The activity of SFKs is deregulated in many types of cancers, and this has been associated with the development, progression, and metastatic dissemination of the tumors.…”

“…Importantly, we showed that YAP/TAZ are effectors of YES-induced hepatocyte transformation in mice. 4

Figure 1. Aberrant YES signaling promotes hepatic oncogenesis.

…”