Role For The Histone Demethylase Kdm4b In Rhabdomyosarcoma Via Cdk6 And Ccna2: Compensation By Kdm4a And Apoptotic Response Of Targeting Both Kdm4b And Kdm4a

Simple SummaryRhabdomyosarcomas (RMS) are soft tissue sarcomas predominant in the pediatric age range. Current standard multi-modal treatments can result in severe life-long side-effects across all subtypes and dismal outcomes in RMS patients classified as high-risk. There is an urgent need to find novel, more targeted therapies for these children. High expression of a number of histone demethylases is shown to support proliferation of RMS cells and here we direct our attention on KDM4B which has become a recent focus for drug discovery efforts. We show that KDM4B regulates cell cycle genes in the context of RMS cells and demonstrate that long-term silencing of KDM4B is functionally compensated for by another KDM4 family member, KDM4A. Upfront reduction of both KDM4A and KDM4B kills RMS cells demonstrating that therapeutics designed to target both histone demethylase family members is desirable to circumvent functional redundancy.Histone demethylases are epigenetic modulators that play key roles in regulating gene expression related to many critical cellular functions and are emerging as promising therapeutic targets in a number of tumor types. We previously identified histone demethylase family members as overexpressed in the pediatric sarcoma, rhabdomyosarcoma. Here we show high sensitivity of rhabdomyosarcoma cells to a pan-histone demethylase inhibitor, JIB-04 and identify a key role for the histone demethylase KDM4B in rhabdomyosarcoma cell growth through an RNAi-screening approach. Decreasing KDM4B levels affected cell cycle progression and transcription of G1/S and G2/M checkpoint genes including CDK6 and CCNA2, which are bound by KDM4B in their promoter regions. However, after sustained knockdown of KDM4B, rhabdomyosarcoma cell growth recovered. We show that this can be attributed to acquired molecular compensation via recruitment of KDM4A to the promoter regions of CDK6 and CCNA2 that are otherwise bound by KDM4B. Furthermore, upfront silencing of both KDM4B and KDM4A led to RMS cell apoptosis, not seen by reducing either alone. To circumvent compensation and elicit stronger therapeutic responses, our study supports targeting histone demethylase sub-family proteins through selective poly-pharmacology as a therapeutic approach.