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P38?/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim.

ABSTRACT: While erythropoietin (EPO) constitutes the major treatment for anemia, a range of anemic disorders remain resistant to EPO treatment. The need for alternative therapeutic strategies requires the identification of mechanisms that physiologically restrain erythropoiesis. Here we show that P38? restrains erythropoiesis in mouse and human erythroblasts independently of EPO by integrating apoptotic signals during recovery from anemia. P38? deficiency promotes JNK activation through increased expression of Map3k4 via a negative feedback mechanism. JNK prevents Cdk1-mediated phosphorylation and subsequent degradation by Smurf2 of the epigenetic silencer Ezh2. Stabilized Ezh2 silences Bim expression and protects erythroblasts from apoptosis. Thus, we identify P38?/JNK signaling as a molecular brake modulating erythropoiesis through epigenetic silencing of Bim. We propose that inhibition of P38?, by enhancing erythropoiesis in an EPO-independent fashion, may provide an alternative strategy for the treatment of anemia.

SUBMITTER: Hu P

PROVIDER: S-EPMC6115418 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim.

Hu Ping P Nebreda Angel R AR Hanenberg Helmut H Kinnebrew Garrett H GH Ivan Mircea M Yoder Mervin C MC Filippi Marie-Dominique MD Broxmeyer Hal E HE Kapur Reuben R

Nature communications 20180829 1

While erythropoietin (EPO) constitutes the major treatment for anemia, a range of anemic disorders remain resistant to EPO treatment. The need for alternative therapeutic strategies requires the identification of mechanisms that physiologically restrain erythropoiesis. Here we show that P38α restrains erythropoiesis in mouse and human erythroblasts independently of EPO by integrating apoptotic signals during recovery from anemia. P38α deficiency promotes JNK activation through increased expressi ...[more]

PMID: 30158520

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Project description:BackgroundUtrophin (UTRN), as a tumor suppressor gene, is involved in various cancer progression. The function of UTRN in the melanoma process and the related molecular mechanisms are still unclear. Herein, we studied the function of UTRN in melanoma growth and the relevant molecular mechanisms.MethodsUsing the GEO database and UCSC Xena project, we compared the expression of UTRN in non-cancerous and melanoma tissues. Immunohistochemistry (IHC) staining, qRT-PCR and Western Blot (WB) were performed to evaluate UTRN expression in clinical samples. A total of 447 cases with UTRN expression data, patient characteristics and survival data were extracted from TCGA database and analyzed. After stable transduction and single cell cloning, the proliferation ability of A375 human melanoma cells was analyzed by Cell Counting Kit‑8 (CCK) and 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assays. GSEA was performed to predict the mechanism by which UTRN regulated melanoma growth. Then WB analysis was used to assess the protein expression levels of pathway signaling in overexpression (EXP) melanoma cells. Epac activator 8-pCPT-2'-O-Me-cAMP was then used to evaluate the proliferation ability by activation of p38 and JNK/c-Jun signaling pathways.ResultsData from GEO and UCSC Xena project indicated that UTRN expression was decreased in melanoma. Experiment on clinical samples further confirmed our finding. TCGA results showed that a reduced expression of UTRN in 447 melanoma samples was associated with advanced clinical characteristics (T stage, Clark level, ulceration), shorter survival time and poorer prognosis. In addition, up-regulated UTRN expression inhibited melanoma cell proliferation when compared to control group. MAPK signaling pathway was presented in both KEGG and BioCarta databases by using GSEA tool. WB results confirmed the down-regulated expression of p38, JNK1 and c-Jun in EXP group when compared to control group. Epac activator 8-pCPT-2'-O-Me-cAMP treatment could partially rescue proliferation of tumor cells.ConclusionWe have demonstrated that reduced UTRN predicted poorer prognosis and UTRN inhibited melanoma growth via p38 and JNK1/c-Jun pathways. Therefore, UTRN could serve as a tumor suppressor and novel prognostic biomarker for melanoma patients.

Dataset Information

P38?/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim.

Publications

P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim.

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