cAMP response element‐binding protein and Yes‐associated protein form a feedback loop that promotes neurite outgrowth

Chen, Lei; Feng, Peimin; Peng, Anjiao; Qiu, Xiangmiao; Zhu, Xi; He, Shixu; Zhou, Dong

doi:10.1111/jcmm.13324

Cited by 19 publications

(19 citation statements)

References 22 publications

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“…Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively. Previous studies have reported interactions between YAP1 and CREB,45, 46 a key mediator of cAMP/PKA signaling, including in liver cancer. CREB transcriptionally activates YAP1, whereas YAP1 promotes protein stability of CREB.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma

Dinh

Jewell

Kanke

et al. 2019

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Fibrolamellar carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. It is characterized by a heterozygous approximately 400-kb deletion on chromosome 19 that results in a unique fusion between DnaJ heat shock protein family member B1 (DNAJB1) and the alpha catalytic subunit of protein kinase A (PRKACA). The role of microRNAs (miRNAs) in FLC remains unclear. We identified dysregulated miRNAs in FLC and investigated whether dysregulation of 1 key miRNA contributes to FLC pathogenesis. Methods We analyzed small RNA sequencing (smRNA-seq) data from The Cancer Genome Atlas to identify dysregulated miRNAs in primary FLC tumors and validated the findings in 3 independent FLC cohorts. smRNA-seq also was performed on a FLC patient-derived xenograft model as well as purified cell populations of the liver to determine whether key miRNA changes were tumor cell–intrinsic. We then used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (Cas9) technology and transposon-mediated gene transfer in mice to determine if the presence of DNAJB1-PRKACA is sufficient to suppress miR-375 expression. Finally, we established a new FLC cell line and performed colony formation and scratch wound assays to determine the functional consequences of miR-375 overexpression. Results We identified miR-375 as the most dysregulated miRNA in primary FLC tumors (27-fold down-regulation; P = .009). miR-375 expression also was decreased significantly in a FLC patient-derived xenograft model compared to 4 different cell populations of the liver. Introduction of DNAJB1-PRKACA by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 engineering and transposon-mediated somatic gene transfer in mice was sufficient to induce significant loss of miR-375 expression ( P < .05). Overexpression of miR-375 in FLC cells inhibited Hippo signaling pathway proteins, including yes-associated protein 1 and connective tissue growth factor, and suppressed cell proliferation and migration ( P < .05). Conclusions We identified miR-375 as the most down-regulated miRNA in FLC tumors and showed that overexpression of miR-375 mitigated tumor cell growth and invasive potential. These findings open a potentially new molecular therapeutic approach. Further studies are necessary to determine how DNAJB1-PRKACA suppresses miR-375 expression and whether miR-375 has additional important targets in this tumor. Transcript profiling: GEO accession numbers: GSE114974 and GSE125602.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma

Dinh

Jewell

Kanke

et al. 2019

Cellular and Molecular Gastroenterology and Hepatology

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“…The Yes-associated protein (YAP) is one of the core effectors of the Salvador–Warts–Hippo (or simply Hippo) signaling pathway, and the other core effector is the transcriptional co-activator with a PDZ-binding motif (TAZ) [ 57 ]. In normal organ tissues, the Hippo/YAP pathway functions to regulate organ size growth control, stem cell function, and regeneration [ 16 , 57 , 58 ]. Deregulation of the Hippo pathway and hyperactivation of YAP are frequently found in a diverse range of cancers, and the Hippo/YAP pathway has been suggested to be involved in cancer initiation and progression [ 16 , 57 ].…”

Section: Hippo/yap Singing Pathway In Nsclcmentioning

confidence: 99%

The Crosstalk between Src and Hippo/YAP Signaling Pathways in Non-Small Cell Lung Cancer (NSCLC)

Hsu

Yang

Jablons

et al. 2020

Cancers

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The advancement of new therapies, including targeted therapies and immunotherapies, has improved the survival of non-small-cell lung cancer (NSCLC) patients in the last decade. Some NSCLC patients still do not benefit from therapies or encounter progressive disease during the course of treatment because they have intrinsic resistance, acquired resistance, or lack a targetable driver mutation. More investigations on the molecular biology of NSCLC are needed to find useful biomarkers for current therapies and to develop novel therapeutic strategies. Src is a non-receptor tyrosine kinase protein that interacts with cell surface growth factor receptors and the intracellular signaling pathway to maintain cell survival tumorigenesis in NSCLC. The Yes-associated protein (YAP) is one of the main effectors of the Hippo pathway and has been identified as a promoter of drug resistance, cancer progression, and metastasis in NSCLC. Here, we review studies that have investigated the activation of YAP as mediated by Src kinases and demonstrate that Src regulates YAP through three main mechanisms: (1) direct phosphorylation; (2) the activation of pathways repressing Hippo kinases; and (3) Hippo-independent mechanisms. Further work should focus on the efficacy of Src inhibitors in inhibiting YAP activity in NSCLC. In addition, future efforts toward developing potentially reasonable combinations of therapy targeting the Src–YAP axis using other therapies, including targeted therapies and/or immunotherapies, are warranted.

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“…Overexpression of YAP has been found in many cancers because of abnormal amplification, loss of Hippo signaling by mutation, and/or downregulation of the core Hippo components. YAP has shown a correlation with stem cell renewal and differentiation, a crucial step in oncogenic transformation [36], and was reported to promote cancer development in various cancers [37,38,39,40].…”

Section: Yes-associated Protein In Human Nsclc and Mpmmentioning

confidence: 99%

The Role of Yes-Associated Protein (YAP) in Regulating Programmed Death-Ligand 1 (PD-L1) in Thoracic Cancer

et al. 2018

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The programmed death-ligand 1(PD-L1)/PD-1 pathway is an immunological checkpoint in cancer cells. The binding of PD-L1 and PD-1 promotes T-cell tolerance and helps tumor cells escape from host immunity. Immunotherapy targeting the PD-L1/PD-1 axis has been developed as an anti-cancer therapy and used in treating advanced human non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Yes-associated protein (YAP) is a key mediator of the Hippo/YAP signaling pathway, and plays important roles in promoting cancer development, drug resistance and metastasis in human NSCLC and MPM. YAP has been suggested as a new therapeutic target in NSCLC and MPM. The role of YAP in regulating tumor immunity such as PD-L1 expression has just begun to be explored, and the correlation between YAP-induced tumorigenesis and host anti-tumor immune responses is not well known. Here, we review recent studies investigating the correlation between YAP and PD-L1 and demonstrating the mechanism by which YAP regulates PD-L1 expression in human NSCLC and MPM. Future work should focus on the interactions between Hippo/YAP signaling pathways and the immune checkpoint PD-L1/PD-1 pathway. The development of new synergistic drugs for immune checkpoint PD-L1/PD-1 blockade in NSCLC and MPM is warranted.

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cAMP response element‐binding protein and Yes‐associated protein form a feedback loop that promotes neurite outgrowth

Cited by 19 publications

References 22 publications

MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma

MicroRNA-375 Suppresses the Growth and Invasion of Fibrolamellar Carcinoma

The Crosstalk between Src and Hippo/YAP Signaling Pathways in Non-Small Cell Lung Cancer (NSCLC)

The Role of Yes-Associated Protein (YAP) in Regulating Programmed Death-Ligand 1 (PD-L1) in Thoracic Cancer

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