A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer

Abstract

SUMMARY Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target genes activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P and this interaction facilitates the recruitment of the MLL1 complex and subsequent H3K4 trimethylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a six-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knock-down or chemical inhibition severely blocks WDR5 association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation, and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and a major driver of androgen-dependent prostate cancer cell proliferation.

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

“…The epigenetic status of prostate cancer cells is modulated by AR binding and the subsequent recruitment of co-activators or co-repressors [14][15][16][17][18] . Acetylation, methylation, phosphorylation, ubiquitylation and ADP ribosylation of histones critically affect transcriptional regulation by ARs [19][20][21] . The main epigenetic mechanism that controls AR binding to DNA in prostate cancer is histone modification by histone acetyltransferases, histone methyltransferases and protein kinases at AR-binding sites (ARBSs) 20,21 .…”

“…Acetylation, methylation, phosphorylation, ubiquitylation and ADP ribosylation of histones critically affect transcriptional regulation by ARs [19][20][21] . The main epigenetic mechanism that controls AR binding to DNA in prostate cancer is histone modification by histone acetyltransferases, histone methyltransferases and protein kinases at AR-binding sites (ARBSs) 20,21 . Specific epigenetic codes modulate opening of chromatin to induce or repress the expression of proteinencoding genes and non-coding RNAs 11 .…”

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

“…Nevertheless, in addition to the previously identified H3S10 dephosphorylation by PP1 [197] and PP2A [198], more recent studies have identified phosphatases for H4S47ph (PP1 and Wip), H3T3ph/S10ph (mitogen activated protein kinase phosphatase 2), and H3T3ph (Repoman/PP1) [199][200][201][202][203][204][205]. Similarly, while earlier studies have identified several phospho-histone binders, such as specific isoforms of 14-3-3 for H3S10ph/S28ph and MDC1 for H2A.XS129ph, more recent studies have identified survivin (H3T3ph), WDR5 (H3T11ph), and shughosin (H2AS120ph) as phospho-histone readers [173,[206][207][208].…”

The biological and clinical advances of androgen receptor function in age-related diseases and cancer [Review]

“…After androgen stimulation, protein kinase C-related kinase 1 (PRK1) promotes histone H3 threonine 11 phosphorylation (H3T11P) [19]. WD repeat containing protein 5 (WDR5), a subunit of the SET1/MLL complex, associates with H3T11P and then promotes the recruitment of the MLL complex for H3K4 tri-methylation (H3K4me3) in ARBSs [20]. PRK1 kinase activity facilitates demethylation of H3K9 by cooperating with lysine-specific demethylase 1 (LSD1) [19,21].…”

“…MLL complex interacts with AR through menin and promotes histone H3K4 methylation to enhance AR dependent gene expression. SRC family or ARA70 are AR interacting cofactors for histone acetylation [18][19][20][21][22][23]. (B) Androgen-induced miRNA mediated TET2 repression inhibits 5-hmC modifications in FOXA1 occupied enhancer regions.…”