Epigenetic Regulation of the PTEN-AKT-RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma
| Autor: | Reshma Taneja, Akshay Bhat, Sudha Suriyamurthy, Vinay Kumar Rao, Luca Pignata, Kenneth Tou En Chang, Ernesto Guccione, Victor Kwan Min Lee, Monica Palanichamy Kala, Huey Jin Lim |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
rac1 GTP-Binding Protein Cancer Research Mice Nude Apoptosis Epigenesis Genetic 03 medical and health sciences Mice 0302 clinical medicine Histocompatibility Antigens medicine Biomarkers Tumor Tumor Cells Cultured PTEN Animals Humans Epigenetics Protein kinase B Rhabdomyosarcoma Alveolar Cell Proliferation Regulation of gene expression biology PTEN Phosphohydrolase Histone-Lysine N-Methyltransferase DNA Methylation medicine.disease Pediatric cancer Xenograft Model Antitumor Assays Chromatin Gene Expression Regulation Neoplastic 030104 developmental biology Oncology 030220 oncology & carcinogenesis DNA methylation Alveolar rhabdomyosarcoma biology.protein Cancer research Female Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cancer research. 79(9) |
| ISSN: | 1538-7445 |
| Popis: | Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with poor prognosis. As transient and stable modifications to chromatin have emerged as critical mechanisms in oncogenic signaling, efforts to target epigenetic modifiers as a therapeutic strategy have accelerated in recent years. To identify chromatin modifiers that sustain tumor growth, we performed an epigenetic screen and found that inhibition of lysine methyltransferase G9a significantly affected the viability of ARMS cell lines. Targeting expression or activity of G9a reduced cellular proliferation and motility in vitro and tumor growth in vivo. Transcriptome and chromatin immunoprecipitation–sequencing analysis provided mechanistic evidence that the tumor-suppressor PTEN was a direct target gene of G9a. G9a repressed PTEN expression in a methyltransferase activity–dependent manner, resulting in increased AKT and RAC1 activity. Re-expression of constitutively active RAC1 in G9a-deficient tumor cells restored oncogenic phenotypes, demonstrating its critical functions downstream of G9a. Collectively, our study provides evidence for a G9a-dependent epigenetic program that regulates tumor growth and suggests targeting G9a as a therapeutic strategy in ARMS. Significance: These findings demonstrate that RAC1 is an effector of G9a oncogenic functions and highlight the potential of G9a inhibitors in the treatment of ARMS. |
| Databáze: | OpenAIRE |
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