A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer

Mol Cell. 2014 May 22;54(4):613-25. doi: 10.1016/j.molcel.2014.03.043. Epub 2014 May 1.

Abstract

Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target gene 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 tri-methylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a 6-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 knockdown or chemical inhibition severely blocks WDR5 chromatin 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 as a major driver of androgen-dependent prostate cancer cell proliferation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androgens / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin / metabolism
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysine / metabolism*
  • Male
  • Methylation
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Phosphorylation
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Signal Transduction
  • Threonine / genetics
  • Threonine / metabolism*

Substances

  • Androgens
  • Chromatin
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • KMT2A protein, human
  • Receptors, Androgen
  • WDR5 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Threonine
  • Histone-Lysine N-Methyltransferase
  • Setd1A protein, human
  • protein kinase N
  • Protein Kinase C
  • Lysine

Associated data

  • GEO/GSE55279