Abstract
Both gene repressor (Polycomb-dependent) and activator (Polycomb-independent) functions of the Polycomb protein enhancer of zeste homolog 2 (EZH2) are implicated in cancer progression. EZH2 protein can be phosphorylated at various residues, such as threonine 487 (T487), by CDK1 kinase, and such phosphorylation acts as a Polycomb repressive complex 2 (PRC2) suppression "code" to mediate the gene repressor-to-activator switch of EZH2 functions. Here we demonstrate that the histone reader protein ZMYND8 is overexpressed in human clear cell renal cell carcinoma (ccRCC). ZMYND8 binds to EZH2, and their interaction is largely enhanced by CDK1 phosphorylation of EZH2 at T487. ZMYND8 depletion not only enhances Polycomb-dependent function of EZH2 in hypoxia-exposed breast cancer cells or von Hippel-Lindau (VHL)-deficient ccRCC cells, but also suppresses the FOXM1 transcription program. We further show that ZMYND8 is required for EZH2-FOXM1 interaction and is important for FOXM1-dependent matrix metalloproteinase (MMP) gene expression and EZH2-mediated migration and invasion of VHL-deficient ccRCC cells. Our results identify a previously uncharacterized role of the chromatin reader ZMYND8 in recognizing the PRC2-inhibitory phosphorylation "code" essential for the Polycomb-dependent to -independent switch of EZH2 functions. They also reveal an oncogenic pathway driving cell migration and invasion in hypoxia-inducible factor-activated (hypoxia or VHL-deficient) cancer.
Highlights
Both gene repressor (Polycomb-dependent) and activator (Polycombindependent) functions of the Polycomb protein enhancer of zeste homolog 2 (EZH2) are implicated in cancer progression
We demonstrate that zinc finger MYND-type containing 8 (ZMYND8) interacts with threonine 487 (T487)-phosphorylated EZH2 and disrupts EZH2 binding with other Polycomb repressive complex 2 (PRC2) components in clear cell renal cell carcinoma (ccRCC) cells
Tang et al ZMYND8 preferentially binds phosphorylated EZH2 to promote a PRC2-dependent to -independent function switch in hypoxia-inducible factor–activated cancer previously [18], we demonstrated that von Hippel–Lindau (VHL) knockdown or hypoxia exposure decreased the expression of PRC2 components SUZ12 and EED, consistent with the decreased level of H3K27me3 (Fig. 1 H and I)
Summary
Both gene repressor (Polycomb-dependent) and activator (Polycombindependent) functions of the Polycomb protein enhancer of zeste homolog 2 (EZH2) are implicated in cancer progression. EZH2 protein can be phosphorylated at various residues, such as threonine 487 (T487), by CDK1 kinase, and such phosphorylation acts as a Polycomb repressive complex 2 (PRC2) suppression “code” to mediate the gene repressor-to-activator switch of EZH2 functions. Our results identify a previously uncharacterized role of the chromatin reader ZMYND8 in recognizing the PRC2-inhibitory phosphorylation “code” essential for the Polycomb-dependent to -independent switch of EZH2 functions. They reveal an oncogenic pathway driving cell migration and invasion in hypoxia-inducible factor–activated (hypoxia or VHL-deficient) cancer. We show that in hypoxia-stimulated or von Hippel–Lindau–deficient cells, ZMYND8 binding of EZH2 is important for maintenance of EZH2 phosphorylation level, inhibition of PRC2 complex formation, and enhanced interaction between EZH2 and FOXM1. ZMYND8 can recognize mutated histone H3.3 (H3.3G34R) detected in pediatric glioblastomas [29]; it is unclear whether ZMYND8 can regulate tumor biology by recognizing posttranslational modifications of nonhistone proteins
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
