ArticleOncogene2018
Protein phosphatase 1 regulatory subunit 1A in ewing sarcoma tumorigenesis and metastasis.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 55 citations in OpenAlex.
- Spatial and Single-Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis.Liver international : official journal of the International Association for the Study of the Liver · 2025Article
- Multi-omics profiling reveals key factors involved in Ewing sarcoma metastasis.Molecular oncology · 2025Article
- Investigating the Causality and Pathogenesis of Primary Sclerosing Cholangitis in Colorectal Cancer Through Mendelian Randomization and Bioinformatics.Genetics research · 2025Article
- Circumventing resistance within the Ewing sarcoma microenvironment by combinatorial innate immunotherapy.Journal for immunotherapy of cancer · 2024Article
- Combinatorial macrophage induced innate immunotherapy against Ewing sarcoma: Turning "Two Keys" simultaneously.Journal of experimental & clinical cancer research : CR · 2024Article
- Role of Protein Phosphatases in Tumor Angiogenesis: Assessing PP1, PP2A, PP2B and PTPs Activity.International journal of molecular sciences · 2024Review
- Cordycepin Triphosphate as a Potential Modulator of Cellular Plasticity in Cancer via cAMP-Dependent Pathways: An In Silico Approach.International journal of molecular sciences · 2024Article
- cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.Journal of hematology & oncology · 2024Review
- Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis.British journal of cancer · 2023Article
- Prognostic value ofHeliyon · 2023Article
- Targeted Therapy for EWS-FLI1 in Ewing Sarcoma.Cancers · 2023Review
- Molecular and biologic biomarkers of Ewing sarcoma: A systematic review.Journal of bone oncology · 2023Review
- A humanized orthotopic mouse model for preclinical evaluation of immunotherapy in Ewing sarcoma.Frontiers in immunology · 2023Article
- Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation.Cell reports · 2022Article
- PPP1R14D promotes the proliferation, migration and invasion of lung adenocarcinoma via the PKCα/BRAF/MEK/ERK signaling pathway.International journal of oncology · 2022Article
- Exploring prognostic value and regulation network of PPP1R1A in hepatocellular carcinoma.Human cell · 2022Article
- Regulation of Metastasis in Ewing Sarcoma.Cancers · 2022Review
- Intra-tumor heterogeneity and prognostic risk signature for hepatocellular carcinoma based on single-cell analysis.Experimental biology and medicine (Maywood, N.J.) · 2022Article
- EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma.Nucleic acids research · 2022Article
- Human EWS-FLI protein recapitulates in Drosophila the neomorphic functions that induce Ewing sarcoma tumorigenesis.PNAS nexus · 2022Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein phosphatase inhibitors are often considered as tumor promoters. Protein phosphatase 1 regulatory subunit 1A (PPP1R1A) is a potent protein phosphatase 1 (PP1) inhibitor; however, its role in tumor development is largely undefined. Here we characterize, for the first time, the functions of PPP1R1A in Ewing sarcoma (ES) pathogenesis. We found that PPP1R1A is one of the top ranked target genes of EWS/FLI, the master regulator of ES, and is upregulated by EWS/FLI via a GGAA microsatellite enhancer element. Depletion of PPP1R1A resulted in a significant decrease in oncogenic transformation and cell migration in vitro as well as xenograft tumor growth and metastasis in an orthotopic mouse model. RNA-sequencing and functional annotation analyses revealed that PPP1R1A regulates genes associated with various cellular functions including cell junction, adhesion and neurogenesis. Interestingly, we found a significant overlap of PPP1R1A-regulated gene set with that of ZEB2 and EWS, which regulates metastasis and neuronal differentiation in ES, respectively. Further studies for characterization of the molecular mechanisms revealed that activation of PPP1R1A by PKA phosphorylation at Thr35, and subsequent PP1 binding and inhibition, was required for PPP1R1A-mediated tumorigenesis and metastasis, likely by increasing the phosphorylation levels of various PP1 substrates. Furthermore, we found that a PKA inhibitor impaired ES cell proliferation, tumor growth and metastasis, which was rescued by the constitutively active PPP1R1A. Together, these results offered new insights into the role and mechanism of PPP1R1A in tumor development and identified an important kinase and phosphatase pathway, PKA/PPP1R1A/PP1, in ES pathogenesis. Our findings strongly suggest a potential therapeutic value of inhibition of the PKA/PPP1R1A/PP1 pathway in the treatment of primary and metastatic ES.
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