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Conference/Presentation Title: | Targeted catalytic inhibition of EZH2 synergizes with low-dose panobinostat in malignant rhabdoid tumor. | Authors: | Cain J.;Downie P. ;Popovski D.;Cochrane C.;Algar E.;Szczepny A.;Jayasekara S.;Ashley D.;Watkins N. | Institution: | (Popovski, Cochrane, Algar, Szczepny, Jayasekara, Cain) Hudson Institute of Medical Research, Clayton, VIC, Australia (Popovski, Cochrane, Algar, Szczepny, Jayasekara, Cain) Monash University, Clayton, VIC, Australia (Ashley) Barwon Health, Geelong, VIC, Australia (Ashley) Deakin University, Geelong, VIC, Australia (Downie) Monash Children's Hospital, Clayton, VIC, Australia (Watkins) Garvan Institute of Medical Research, Darlinghurst, NSW, Australia | Presentation/Conference Date: | 16-Feb-2018 | Copyright year: | 2017 | Publisher: | Oxford University Press | Publication information: | Neuro-Oncology. Conference: 4th Biennial Conference on Pediatric Neuro-Oncology Basic and Translational Research. New York City, NY United States. 19 (Supplement 4) (pp iv1), 2017. Date of Publication: June 2017. | Abstract: | Malignant Rhabdoid Tumor (MRT) is a rare pediatric cancer predominantly occurring in the kidney and CNS that is highly resistant to current treatment protocols. MRT is almost exclusively characterized by homozygous inactivation of SMARCB1, a critical subunit of the SWI/SNF chromatin-remodeling complex, implicating epigenetic deregulation in the pathogenesis of the disease. Recently, we showed that sustained treatment of human MRT cell lines with the Histone deacetylase inhibitor, Panobinostat, at low-dose, inhibited tumor growth by driving multi-lineage differentiation in vitro and in vivo. Furthermore, re-expression of SMARCB1 in MRT cells phenocopied low-dose Panobinostat treatment and led to growth inhibition, senescence and terminal differentiation in vitro and in vivo, suggesting similar mechanistic functionality. Enhancer of Zeste homolog 2 (EZH2), a core subunit of the Polycomb Repressive Complex 2, confers transcriptional silencing via the addition of methyl groups to Lysine 27 of Histone 3 (H3K27me3), and is a transcriptional target of SMARCB1. EZH2 expression and H3K27me3 were drastically reduced following sustained low-dose Panobinostat treatment and re-expression of SMARCB1 in MRT cells. Sustained siRNA knockdown of EZH2 in G401 cells resulted in reduced cell growth and changes in mRNA expression, mimicking low-dose Panobinostat treatment and SMARCB1 re-expression. Treatment of MRT cells with the EZH2-catalytic domain inhibitors, GSK126, GSK343 and UNC1999, had no effect on EZH2 expression and only partially reduced cell growth despite dose-dependent reductions in H3K27me3 implying important non-catalytic EZH2 function. Remarkably, co-treatment of MRT with low-dose Panobinostat and GSK126 resulted in reduced EZH2 and H3K27me3 expression, significantly reduced cell growth and increased differentiation in vitro and in vivo compared to single agent controls, demonstrating a synergistic relationship. This data suggests EZH2 is an important mediator of MRT proliferation and differentiation and provides evidence for improved efficacy of dual therapeutic targeting of EZH2 with low-dose Panobinostat. | Conference Start Date: | 2017-06-15 | Conference End Date: | 2017-06-16 | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1093/neuonc/nox083 | ISSN: | 1523-5866 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/38963 | Type: | Conference Abstract | Subjects: | *rhabdoid tumor cell line senescence tumor growth BRM protein cancer resistance endogenous compound histone H3 lysine messenger RNA *panobinostat polycomb repressive complex 2 *catalysis SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily B member 1 *transcription factor EZH2 conference abstract small interfering RNA central nervous system child clinical protocol controlled clinical trial controlled study deregulation differentiation drug therapy enzyme active site epigenetics gene silencing genetic association growth inhibition homozygosity human human cell in vitro study in vivo study kidney low drug dose mediator homozygosity human human cell in vitro study in vivo study kidney low drug dose mediator *rhabdoid tumor cell line senescence controlled study controlled clinical trial clinical protocol child central nervous system *catalysis cancer resistance tumor growth deregulation differentiation drug therapy enzyme active site epigenetics gene silencing genetic association growth inhibition |
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