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  • Recent efforts have also tried to identify

    2021-10-12

    Recent efforts have also tried to identify cancer subsets that are exquisitely responsive to EZH2i apart from those bearing EZH2 gene mutation (Knutson et al., 2012). The dysfunction of SWI-SNF complex, a chromatin-remodeling regulator that partially antagonizes the catalytic function of PRC2 complex, has been demonstrated to sensitize cancer ER 27319 maleate to EZH2i treatment both in vitro and in vivo; loss of function of the components of the SWI-SNF complex—mainly BRG1, Arid1A, SMARCA4, or INI1—renders cancer cells from several solid tumor types’ responsiveness to EZH2is in vitro and in vivo (Bitler et al., 2015, Fillmore et al., 2015, Kim et al., 2015, Zhang et al., 2014). PRC2 also antagonizes the histone modification of demethylase JMJD3/UTX and transcriptionally regulates the TrxG and p300/CBP complexes. However, it remains unclear how these opposing complexes cooperatively maintain the intrinsic balance of epigenetic modulations and whether the interaction between these complexes and related histone modifications are important to the response to EZH2i.
    Results
    Discussion Histone modifications are important epigenetic signatures that dictate gene expression states, cell identities in cancer, and the drug response to the treatment (Filippakopoulos and Knapp, 2014, Kim and Roberts, 2016). In this study, we show that the intervention of a single epigenetic enzyme like EZH2 can regulate a set of epigenetic enzymes and thereby influence own- or ortho-position modifications. The secondary epigenetic effect could lead to a propagating wave in histone modifications and defines the ultimate histone modification pattern. A previous study has reported that the NSD2 activity change could affect numerous histone modifications (Jaffe et al., 2013). We now report that EZH2i could lead to a global landscape change of histone marks. For instance, 45 histone marks were changed by more than 2-fold in our tested cell lines (Figure 1A). Among the globally altered histone marks, a specific interplay between H3K27me and H3K27ac was noted and shown to be critical for determining the drug response to the EZH2 inhibition, suggesting an intrinsic preference of histone modification crosstalk. For example, we have shown that H3K27me loss did not lead to a switch to other types of histone modifications occurring on the same residue, such as H3K27pr (Figure 1A), further supporting the existence of a distinct regulatory mechanism that specifically connects H3K27me loss to H3K27ac. The H3K27me and H3K27ac crosstalk has been previously reported as an antagonistic switch on the same H3K27 residue in a small tumor subset—mostly hematological malignancies (Knutson et al., 2012, Lee et al., 2014, Pasini et al., 2010, Zhang et al., ER 27319 maleate 2014). We substantially extend earlier observations in cancer scope and mechanistically by showing that MLL1 forms a complex with p300 and facilitates p300-catalyzed H3K27ac upon PRC2 inhibition. Depletion of MLL1 fails to allow a switch from H3K27me to H3K27ac. All these collectively suggest an “on-off” switch for histone modifications that stringently requires MLL1. MLL1 is generally believed to be present in multiple epigenetic complexes and is involved in the modification of various types of histone marks. MLL1 homolog was reported to be present in the TrxG complex that controls the on-off switch for gene transcription. A previous study suggested that MLL1 monomethylated histone H3K4 could promote H3K27ac (Tie et al., 2014). Our findings advance this understanding by showing that the intrinsic presence of MLL1 functions as an adaptor protein complexed with p300 that directs H3K27me loss to the gain of H3K27ac modification, regardless of H3K4me status. The intrinsic MLL1 level varies between the different cancers (data not shown), which may largely explain the differential H3K27ac response despite the similar suppressed H3K27me. A previous work by De Raedt et al. (2014) has shown that loss of PRC2 function leads to RAS-MAPK signaling activation in subsets of malignant peripheral nerve sheath tumor (MPMST) with PRC2 (SUZ12/EED) loss and NF1 mutation. In our current study, the exploration of a broader cancer context allows us to obtain a more complete picture of RAS signaling activation upon loss of PRC2 function. At least three major scenarios exist. In some cells, like Pfeiffer cells, RAS/MAPK signaling is not increased upon EZH2i. U2932 cells represent another situation that echoes the findings by De Raedt in which Ras/MAPK signaling is activated via EZH2i-induced H3K27ac upregulation and inhibition of H3K27ac could block its activation. Apart from these two situations, there is another possibility that occurs more often in which the concurrent inhibition of H3K27ac with PRC2 could lead to a feedback activation of Ras/MAPK signaling via a different mechanism, such as the transcriptionally decreased ERK1. These findings provide an example that demonstrates the differential response of onco-pathways upon epigenetic modulation, highlighting the importance to carefully dissect the situation for the therapeutic benefit.