PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism.

TitlePFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism.
Publication TypeJournal Article
Year of Publication2019
AuthorsJain, SU, Do, TJ, Lund, PJ, Rashoff, AQ, Diehl, KL, Cieslik, M, Bajic, A, Juretic, N, Deshmukh, S, Venneti, S, Muir, TW, Garcia, BA, Jabado, N, Lewis, PW
JournalNat Commun
Volume10
Issue1
Pagination2146
Date Published2019 05 13
ISSN2041-1723
KeywordsAnimals, Brain Neoplasms, Carcinogenesis, Cell Line, Tumor, Chromatin, CpG Islands, Cranial Fossa, Posterior, Datasets as Topic, Embryo, Mammalian, Ependymoma, Fibroblasts, Gene Expression Regulation, Neoplastic, Gene Silencing, Glioma, HEK293 Cells, Histones, Humans, Mice, Oncogene Proteins, Polycomb Repressive Complex 2, Primary Cell Culture, Recombinant Proteins
Abstract

Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). Here we find that a conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promotes similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at CpG islands. We find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a mechanism to explain the observed loss of H3K27me3 spreading in tumors. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors, the K27M oncohistone and the EZHIP 'oncohistone-mimic', that dysregulate gene silencing to promote tumorigenesis.

DOI10.1038/s41467-019-09981-6
Alternate JournalNat Commun
PubMed ID31086175
PubMed Central IDPMC6513997
Grant List2016100 / / Doris Duke Charitable Foundation (DDCF) / International
K08 CA181475 / CA / NCI NIH HHS / United States
T32 GM008692 / GM / NIGMS NIH HHS / United States
T32 CA009140 / CA / NCI NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
444000 / / Sidney Kimmel Foundation / International
DP2 OD007447 / OD / NIH HHS / United States
R01 GM110174 / GM / NIGMS NIH HHS / United States
791165 / / Sontag Foundation / International