PI3K/Akt/YAP signaling promotes migration and invasion of DLD‑1 colorectal cancer cells

Takeda, Tomoya; Yamamoto, Yuuta; Tsubaki, Masanobu; Matsuda, Takuya; Kimura, Akihiro; Shimo, Natsumi; Nishida, Shozo

doi:10.3892/ol.2022.13226

Cited by 11 publications

(7 citation statements)

References 39 publications

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“…The key role played by YAP in cell migration, both in development and in cancer metastasis, has been well documented [ 1 , 38 , 48 ], but the molecular mechanisms involved in its regulation remain poorly described [ 49 ]. We therefore tested the role of ERK5 in the YAP-induced migration of HuH7 cells that display, together with an epithelial phenotype, a low rate of motility.…”

Section: Resultsmentioning

confidence: 99%

Extracellular signal-Regulated Kinase 5 (ERK5) is required for the Yes-associated protein (YAP) co-transcriptional activity

et al. 2023

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YES-associated protein (YAP) is a transcriptional cofactor with a key role in the regulation of several physio-pathological cellular processes, by integrating multiple cell autonomous and microenvironmental cues. YAP is the main downstream effector of the Hippo pathway, a tumor-suppressive signaling able to transduce several extracellular signals. The Hippo pathway acts restraining YAP activity, since its activation induces YAP phosphorylation and cytoplasmic sequestration. However, recent observations indicate that YAP activity can be also modulated by Hippo independent/integrating pathways, still largely unexplored. In this study, we demonstrated the role of the extracellular signal-regulated kinase 5 (ERK5)/mitogen-activated protein kinase in the regulation of YAP activity. By means of ERK5 inhibition/silencing and overexpression experiments, and by using as model liver stem cells, hepatocytes, and hepatocellular carcinoma (HCC) cell lines, we provided evidence that ERK5 is required for YAP-dependent gene expression. Mechanistically, ERK5 controls the recruitment of YAP on promoters of target genes and its physical interaction with the transcriptional partner TEAD; moreover, it mediates the YAP activation occurring in cell adhesion, migration, and TGFβ-induced EMT of liver cells. Furthermore, we demonstrated that ERK5 signaling modulates YAP activity in a LATS1/2-independent manner. Therefore, our observations identify ERK5 as a novel upstream Hippo-independent regulator of YAP activity, thus unveiling a new target for therapeutic approaches aimed at interfering with its function.

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Section: Resultsmentioning

confidence: 99%

Extracellular signal-Regulated Kinase 5 (ERK5) is required for the Yes-associated protein (YAP) co-transcriptional activity

et al. 2023

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“…Previous studies have shown that FGFR4 signaling inhibits the activity of YAP by phosphorylating the upstream MST1/2 [ 34 ]. In addition, YAP expression was also induced by PI3K/AKT signaling, which was also repressed along with FGFR4 inhibition [ 35 , 36 ]. However, in the present study, we found that the phosphorylation of MST1/2 and LAST1/2 was only slightly changed after the addition of FGFR4 inhibitor (Fig.…”

Section: Discussionmentioning

confidence: 99%

FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling

Yang

Zhang

Cao

et al. 2023

J Exp Clin Cancer Res

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Background Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, but current treatment options remain limited and cause serious life-threatening side effects. Aberrant FGFR4 signaling has been validated as an oncogenic driver of HCC, and EZH2, the catalytic subunit of the PRC2 complex, is a potential factor that contributes to acquired drug resistance in many tumors, including HCC. However, the functional relationship between these two carcinogenic factors, especially their significance for HCC treatment, remains unclear. In this study, we systematically evaluated the feasibility of a combination therapy targeting FGFR4 and EZH2 for HCC. Methods RNA sequencing data of patients with Liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA) were analyzed to determine FGFR4 and EZH2 expression and their interaction with prognosis. Moreover, the HCC cell lines, zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors were treated with FGFR4 inhibitor (Roblitinib) and/or EZH2 inhibitor (CPI-169) and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for HCC both in vitro and in vivo. Furthermore, RNA-Seq was performed in combination with ChIP-Seq data analysis to investigate the critical mechanism underlying the combination treatment with Roblitinib and CPI-169. Results EZH2 accumulated through the non-canonical NF-kB signaling in response to FGFR4 inhibitor treatment, and the elevated EZH2 levels led to the antagonism of HCC against Roblitinib (FGFR4 inhibitor). Notably, knockdown of EZH2 sensitized HCC cells to Roblitinib, while the combination treatment of Roblitinib and CPI-169 (EZH2 inhibitor) synergistically induced the HCC cell apoptosis in vitro and suppressed the zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors development in vivo. Moreover, Roblitinib and CPI-169 synergistically inhibited HCC development via repressing YAP signaling. Conclusions Collectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC.

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“…An effector of this pathway, mTOR, phosphorylates the Hippo pathway and favors YAP1 activity, stimulating the proliferation and invasion of glioblastoma cells ( 79 ). In colorectal cancer, the PI3K/AKT pathway activates YAP1, leading to increased invasion and migration ( 80 ).…”

Section: Key Factors In Rr and The Hippo Pathwaymentioning

confidence: 99%

Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review)

Taylor,

Dubois,

Bergot

et al. 2024

Int J Oncol

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The prognosis for patients with non-small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5-year survival rate of 19%, mainly because NSCLC is diagnosed at an advanced and metastatic stage. Despite recent therapeutic advancements, ~50% of patients with NSCLC will develop brain metastases (BMs). Either surgical BM treatment alone for symptomatic patients and patients with single cerebral metastases, or in combination with stereotactic radiotherapy (RT) for patients who are not suitable for surgery or presenting with fewer than four cerebral lesions with a diameter range of 5-30 mm, or whole-brain RT for numerous or large BMs can be administered. However, radioresistance (RR) invariably prevents the action of RT. Several mechanisms of RR have been described including hypoxia, cellular stress, presence of cancer stem cells, dysregulation of apoptosis and/or autophagy, dysregulation of the cell cycle, changes in cellular metabolism, epithelial-to-mesenchymal transition, overexpression of programmed cell death-ligand 1 and activation several signaling pathways; however, the role of the Hippo signaling pathway in RR is unclear. Dysregulation of the Hippo pathway in NSCLC confers metastatic properties, and inhibitors targeting this pathway are currently in development. It is therefore essential to evaluate the effect of inhibiting the Hippo pathway, particularly the effector yes-associated protein-1, on cerebral metastases originating from lung cancer.

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PI3K/Akt/YAP signaling promotes migration and invasion of DLD‑1 colorectal cancer cells

Cited by 11 publications

References 39 publications

Extracellular signal-Regulated Kinase 5 (ERK5) is required for the Yes-associated protein (YAP) co-transcriptional activity

Extracellular signal-Regulated Kinase 5 (ERK5) is required for the Yes-associated protein (YAP) co-transcriptional activity

FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling

Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review)

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