ROLE OF G9A LYSINE METHYLTRANSFERASE IN ALVEOLAR RHABDOMYOSARCOMA

Abstract

Alveolar Rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer with poor prognosis. Several epigenetic perturbances have been implicated in the pathogenesis of ARMS. However, the role of G9a, a lysine methyl transferase which catalyses histone H3K9 di-methylation has not been studied. We found that G9a expression is elevated in patient tumor specimens and cell lines. Targeting G9a expression or activity reduced cellular proliferation and motility in vitro and tumor growth in vivo. Using transcriptome and chromatin immunoprecipitation-sequencing analysis, we provide evidence that the tumor suppressor PTEN is a direct G9a target gene. G9a represses PTEN expression in a methyltransferase activity-dependent manner resulting in increased AKT and RAC1 activity. Interestingly, re-expression of constitutively active RAC1 in G9a-deficient tumor cells restores oncogenic phenotypes, demonstrating its critical function downstream of G9a. Our study provides evidence for a G9a-dependent epigenetic program that regulates tumor growth. We propose targeting G9a as a therapeutic strategy in ARMS.