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Conference/Presentation Title: | Targeted catalytic inhibition of EZH2 synergizes with low-dose HDACi in malignant rhabdoid tumors. | Authors: | Algar E.M.;Cochrane C.R.;Szczepny A.;Jayasekara W.S.;Ashley D.M.;Downie P. ;Watkins D.N.;Cain J.E.;Popovski D. | Institution: | (Popovski, Algar, Cochrane, Szczepny, Jayasekara, Cain) Hudson Institute of Medical Research, Clayton, Australia (Ashley) Barwon Health, Geelong, Australia (Downie) Monash Children's Hospital, Clayton, Australia (Watkins) Garvan Institute of Medical Research, Darlinghurst, Australia | Presentation/Conference Date: | 9-Oct-2017 | Copyright year: | 2017 | Publisher: | American Association for Cancer Research Inc. | Publication information: | Cancer Research. Conference: American Association for Cancer Research Annual Meeting 2017. Washington, DC United States. 77 (13 Supplement 1) (no pagination), 2017. Date of Publication: July 2017. | Abstract: | Malignant Rhabdoid Tumor (MRT) is a rare pediatric cancer of the kidney and CNS that is resistant to current treatment protocols. MRT is genetically characterized by homozygous inactivation of SMARCB1, a critical subunit of the SWI/SNF chromatin-remodeling complex. Next-generation sequencing data suggests that inactivation of SMARCB1 is the primary driver mutation, implicating epigenetic deregulation in the pathogenesis of MRT. Recently, we showed that sustained treatment of MRT cell lines with low-dose Panobinostat (LBH589), inhibited tumor growth by driving multi-lineage differentiation in vitro and in vivo. Furthermore, re-expression of physiological levels of SMARCB1 in G401 MRT cells phenocopied the low-dose LBH589 treatment and led to growth inhibition, senescence and terminal differentiation in vitro and in vivo. Enhancer of Zeste homolog 2 (EZH2), a core subunit of the Polycomb Repressive Complex 2 (PRC2), confers transcriptional silencing via the addition of methyl groups to Lysine 27 of Histone 3 (H3K27me ), and is a transcriptional target of SMARCB1. EZH2 expression and H3K27me were drastically reduced following sustained low-dose LBH589 treatment and re-expression of SMARCB1 in G401 MRT cells. Sustained siRNA knockdown of EZH2 in G401 cells resulted in reduced cell growth and changes in mRNA expression similar to those observed following low-dose LBH589 treatment and SMARCB1 re-expression. Treatment of MRT cells with the EZH2-catalytic domain inhibitor, GSK-126, had no effect on EZH2 expression and only partially reduced H3K27me and cell growth at doses 1nM-10muM suggesting important non-catalytic EZH2 function. However, MRT cells treated in combination with low-dose LBH589 and GSK-126, lost EZH2 and H3K27me expression and exhibited significantly reduced cell growth in vitro compared to single agent controls, revealing a synergistic relationship. Similar effects were observed in an in vivo xenograft model, with low-dose LBH589 and GSK-126 treatment leading to a marked reduction in tumor growth, not observed with single agent treatment. This data suggests EZH2 is an important mediator of MRT proliferation and differentiation and provides evidence for dual therapeutic targeting of EZH2 with low-dose HDACi in MRT. | Conference Start Date: | 2017-04-01 | Conference End Date: | 2017-04-05 | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1158/1538-7445.AM2017-3360 | ISSN: | 1538-7445 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/39081 | Type: | Conference Abstract | Subjects: | in vivo study low drug dose major clinical study mediator next-generation sequencing *rhabdoid tumor cell line senescence tumor growth xenograft BRM protein endogenous compound histone H3 lysine messenger RNA *panobinostat polycomb repressive complex 2 SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily B member 1 *transcription factor EZH2 kidney small interfering RNA animal model cancer resistance *catalysis central nervous system child clinical protocol controlled study deregulation differentiation driver drug therapy enzyme active site epigenetics gene mutation gene silencing growth inhibition homozygosity human human cell in vitro study gene silencing clinical protocol homozygosity human human cell in vitro study in vivo study kidney low drug dose major clinical study mediator next generation sequencing *rhabdoid tumor cell line senescence tumor growth xenograft child central nervous system *catalysis cancer resistance animal model growth inhibition controlled study deregulation differentiation driver drug therapy enzyme active site epigenetics gene mutation |
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