The crosstalk between AXL and YAP promotes tumor progression through STAT3 activation in head and neck squamous cell carcinoma

Abstract

Receptor tyrosine kinases (RTKs) and Yes‐associated protein (YAP) are critical driving factors in tumors. Currently, the regulation of RTKs in the Hippo‐YAP pathway has been recognized as an important issue. However, the relationship between AXL, one of the RTKs, and YAP in head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, the crosstalk between AXL and YAP was thoroughly investigated in vitro and in vivo. We determined that there was a positive correlation between AXL and YAP in the HNSCC tissue samples and the Cancer Genome Atlas (TCGA) dataset, and high co‐expression was associated with poor prognosis. Inhibiting YAP decreased AXL expression in HNSCC cells, while YAP overexpression increased AXL. Moreover, ectopic expression of AXL reversed tumor suppressor phenotypes mediated by YAP silencing. This reversal effect was also confirmed in vivo. In addition, AXL overexpression and Gas6, a ligand of AXL, stimulated YAP dephosphorylation, nuclear translocation, and target gene transcription. AXL inhibition decreased YAP dephosphorylation and nuclear translocation. Mechanistically, Gas6 induced a competitive binding to phosphorylated signal transducers and activators of transcription 3 (STAT3) with large tumor suppressor kinase 1 (LATS1) and inhibited the Hippo pathway. This study revealed a novel non‐transcriptional effect of STAT3 in Gas6/AXL‐induced YAP activity, suggesting that STAT3 acted as a critical “molecular switch” during the mutual promotion between AXL and YAP, which might be a promising therapeutic target in HNSCC.

E6AP is important for HPV E6’s role in regulating epithelial homeostasis and its loss impairs keratinocyte commitment to differentiation

“…qPCR was then performed to quantify to verify the relative abundance of YAP downstream gene expression. Consistent with the RNA-seq outcome, well-characterised YAP target genes AREG, PLAU, PTGS2, AXL and CTGF that were described in previous literature (Corley et al, 2018; Franklin et al, 2020; H. Kim et al, 2021; Li et al, 2020), were expressed at 2-to 20-fold higher levels when E6AP was depleted (figure 7C). All these genes have indicated functions in driving cell proliferation.…”

YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations

“…Most notably, this includes YAP and TEAD1, with YAP's regulatory role most significantly determined in the mesothelioma cell line, NCI‐H2052 (top two p‐ values, each < .0001) and TEAD1 also yielding a highly significant association ( p < .0001) in the MSTO mesothelioma line. Additional transcriptional regulators found significantly associated with gene‐set regulation include STAT3, which is known to bind to and regulate YAP/TAZ, 104 , 105 and FOSL2 and JUN, two components of the AP‐1 transcriptional complex, which co‐localises with YAP, TAZ, and TEAD at transcriptional enhancer sites. 53 , 106 Importantly, all three of these regulators recruit YAP/TAZ, orchestrating the transcription of YAP/TAZ target genes in transformed cells.…”

Role of the Hippo‐YAP/NF‐κB signaling pathway crosstalk in regulating biological behaviors of macrophages under titanium ion exposure

“…YAP is a key downstream molecule of the Hippo pathway, which can interfere with many signaling pathways, thus participating in the regulation of cell proliferation, cell differentiation, and inflammatory response (Li et al, 2020;Manning, Kroeger, & Harvey, 2020;Zhang et al, 2020). In addition, the regulatory role of NF-κB in inflammation has been confirmed.…”