Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex

Prostate. 2013 Apr;73(5):455-66. doi: 10.1002/pros.22587. Epub 2012 Oct 4.

Abstract

Background: Chromatin regulators ANCCA and EZH2 are overexpressed in prostate cancer and play crucial roles in androgen-stimulated and castration-refractory prostate tumor growth and survival. However, how their expression is regulated in the tumors and whether they play a role in prostate development remains unclear.

Methods: Prostate tissue from different developmental stages of mouse and human were examined by IHC, qRT-PCR and Western for expression of ANCCA, EZH2, and Ki-67. Animals were castrated and T-implanted for the expression response in normal prostate and tumors. siRNA knockdown and ChIP were performed for the mechanism of ANCCA regulation of EZH2.

Results: In contrast to their very low level expression in adult prostate, ANCCA and EZH2 are strongly expressed in the epithelium and mesenchyme of mouse and human UGS. Their expression becomes more restricted to epithelial cells during later development and displays a second peak during puberty, which correlates with the proliferative status of the epithelium. Importantly, their expression in normal prostate and tumors is strongly suppressed by castration and markedly induced by testosterone replacement. While androgen suppresses EZH2 in CRPC cells, in LNCaP cells, physiological concentrations of androgen stimulate expression of PRC2 genes (EZH2, SUZ12, and EED), which is mediated by androgen-induced ANCCA and involves E2F and histone H3K4me3 methylase MLL1 complex.

Conclusion: EZH2 and ANCCA are androgen regulated and strongly expressed in early prostate morphogenesis and during puberty, suggesting their important role in prostate development. Regulation of EZH2 by ANCCA emphasizes bromodomain protein ANCCA as a potential therapeutic target against prostate cancer.

Publication types

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

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Androgens / metabolism*
  • Animals
  • Cell Line, Tumor
  • Chromatin / enzymology
  • Chromatin / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • Gene Expression Regulation, Developmental / physiology
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Multienzyme Complexes / metabolism*
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Neoplasm Transplantation
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism*
  • Pregnancy
  • Prostate* / embryology
  • Prostate* / metabolism
  • Prostate* / pathology
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • RNA, Small Interfering / genetics
  • Sexual Maturation / physiology
  • Transplantation, Heterologous

Substances

  • Androgens
  • Chromatin
  • DNA-Binding Proteins
  • KMT2A protein, human
  • Multienzyme Complexes
  • RNA, Small Interfering
  • Myeloid-Lymphoid Leukemia Protein
  • Histone Methyltransferases
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2
  • Adenosine Triphosphatases
  • ATAD2 protein, human
  • ATAD2 protein, mouse
  • ATPases Associated with Diverse Cellular Activities