Glioblastoma stem cells reprogram chromatin in vivo to generate selective therapeutic dependencies on DPY30 and phosphodiesterases
Deobrat Dixit, Briana C. Prager, Ryan C. Gimple, Tyler E. Miller, Qiulian Wu, Shira Yomtoubian, Reilly L. Kidwell, Deguan Lv, Linjie Zhao, Zhixin Qiu, Guoxin Zhang, Derrick Lee, Donglim Esther Park, Robert J. Wechsler‐Reya, Xiuxing Wang, Shideng Bao, Jeremy N. Rich
Abstract
, and phosphodiesterase (PDE) family members. In intracranial PDX tumors, DPY30 regulated angiogenesis and hypoxia pathways in an H3K4me3-dependent manner but was dispensable in vitro in cultured GSCs. PDE4B was a key downstream effector of DPY30, and the PDE4 inhibitor rolipram preferentially targeted DPY30-expressing cells and impaired PDX tumor growth in mice without affecting tumor cells cultured in vitro. Collectively, the MLL/SET1 (mixed lineage leukemia/SET domain-containing 1, histone lysine methyltransferase) complex member DPY30 selectively regulates H3K4me3 modification on genes critical to support angiogenesis and tumor growth in vivo, suggesting the DPY30-PDE4B axis as a specific therapeutic target in glioblastoma.