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Phosphorylation of 14-3-3? links YAP transcriptional activation to hypoxic glycolysis for tumorigenesis.

ABSTRACT: Hypoxic microenvironment deregulates metabolic homeostasis in cancer cells albeit the underlying mechanisms involved in this process remain hitherto enigmatic. 14-3-3?/Yes-associated protein (YAP) axis plays a principal role in malignant transformation and tumor development. Here, we report that hypoxia disassembles 14-3-3? from YAP and thereby promotes YAP nuclear localization mediated by ERK2, which directly binds to the D-site of mitogen-activated protein kinase (MAPK) docking domain in 14-3-3? Leu98/100 and phosphorylates 14-3-3? at Ser37. When localizing in nucleus, YAP recruits at pyruvate kinase M2 (PKM2) gene promoter with hypoxia-inducible factor 1? (HIF-1?), for which PKM2 transcription is required. 14-3-3? Ser37 phosphorylation is instrumental for the hypoxia-induced glucose uptake, lactate production, and clonogenicity of pancreatic ductal adenocarcinoma (PDAC) cells, as well as tumorigenesis in mice. The 14-3-3? Ser37 phosphorylation positively correlates with p-ERK1/2 activity and HIF-1? expression in clinical samples from patients with PDAC and predicts unfavorable prognosis. Our findings underscore an appreciable linkage between YAP transcriptional activation and hypoxic glycolysis governed by ERK2-dependent 14-3-3? Ser37 phosphorylation for malignant progression of PDAC.

SUBMITTER: Jia Y

PROVIDER: S-EPMC6510816 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Phosphorylation of 14-3-3ζ links YAP transcriptional activation to hypoxic glycolysis for tumorigenesis.

Jia Yu Y Li Hui-Yan HY Wang Jue J Wang Ying Y Zhang Peng P Ma Ning N Mo Shi-Jing SJ

Oncogenesis 20190510 5

Hypoxic microenvironment deregulates metabolic homeostasis in cancer cells albeit the underlying mechanisms involved in this process remain hitherto enigmatic. 14-3-3ζ/Yes-associated protein (YAP) axis plays a principal role in malignant transformation and tumor development. Here, we report that hypoxia disassembles 14-3-3ζ from YAP and thereby promotes YAP nuclear localization mediated by ERK2, which directly binds to the D-site of mitogen-activated protein kinase (MAPK) docking domain in 14-3- ...[more]

PMID: 31076568

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Project description:BackgroundCircular RNA (circRNA), a new class of non-coding RNA, has obvious correlations with the occurrence and development of many diseases, including tumors. This study aimed to investigate the potential roles of circPAK1 in hepatocellular carcinoma (HCC).MethodsHigh-throughput sequencing was performed on 3 pairs of HCC and matched normal tissues to determine the upregulated circRNAs. The expression level of circPAK1 was detected by qRT-PCR in HCC and paired with normal liver tissue samples. The effects of circPAK1 on proliferation, invasion, metastasis and apoptosis of HCC cells were evaluated by in vitro and in vivo experiments. We also constructed Chitosan/si-circPAK1 (CS/si-circPAK1) nanocomplexes using Chitosan material to evaluate its in vivo therapeutic effect on HCC. High-throughput sequencing, RNA-sequencing, RNA probe pull-down, RNA immunoprecipitation and Co-Immunoprecipitation assays were performed to explore the relationship between circPAK1, 14-3-3ζ, p-LATS1 and YAP. Exosomes isolated from lenvatinib-resistant HCC cell lines were used to evaluate the relationship between exosomal circPAK1 and lenvatinib resistance.ResultsCircPAK1, a novel circRNA, is highly expressed in HCC tumor tissues and cell lines as well as correlated with poor outcomes in HCC patients. Functionally, circPAK1 knockdown inhibited HCC cell proliferation, migration, invasion and angiogenesis while circPAK1 overexpression promoted HCC progression. The tumor-promoting phenotypes of circPAK1 on HCC were also confirmed by animal experiments. Importantly, the application of CS/si-circPAK1 nanocomplexes showed a better therapeutic effect on tumor growth and metastasis. Mechanistically, circPAK1 enhanced HCC progression by inactivating the Hippo signaling pathway, and this kind of inactivation is based on its competitively binding of 14-3-3 ζ with YAP, which weakens the recruitment and cytoplasmic fixation of 14-3-3 ζ to YAP, thus promoting YAP nucleus localization. Additionally, circPAK1 could be transported by exosomes from lenvatinib-resistant cells to sensitive cells and induce lenvatinib resistance of receipt cells.ConclusionCircPAK1 exerts its oncogenic function by competitively binding 14-3-3 ζ with YAP, thus promoting YAP nucleus localization, leading to the inactivation of a Hippo signaling pathway. Exosomal circPAK1 may drive resistance to lenvatinib, providing a potential therapeutic target for HCC patients.

Dataset Information

Phosphorylation of 14-3-3? links YAP transcriptional activation to hypoxic glycolysis for tumorigenesis.

Publications

Phosphorylation of 14-3-3ζ links YAP transcriptional activation to hypoxic glycolysis for tumorigenesis.

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