Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma

Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma
Title:
Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma
Other Titles:
Cancer Research
Keywords:
Publication Date:
01 May 2019
Citation:
Epigenetic Regulation of the PTEN–AKT–RAC1 Axis by G9a Is Critical for Tumor Growth in Alveolar Rhabdomyosarcoma Akshay V. Bhat, Monica Palanichamy Kala, Vinay Kumar Rao, Luca Pignata, Huey Jin Lim, Sudha Suriyamurthy, Kenneth T. Chang, Victor K. Lee, Ernesto Guccione and Reshma Taneja Cancer Res May 1 2019 (79) (9) 2232-2243; DOI: 10.1158/0008-5472.CAN-18-2676
Abstract:
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.
License type:
Publisher Copyright
Funding Info:
This research / project is supported by the National Medical Research Council - National Medical Research Council grant
Grant Reference no. : NMRC/CBRG/0063/2014
Description:
ISSN:
0008-5472
1538-7445
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