Title | The phytochemical 3,3'-diindolylmethane decreases expression of AR-controlled DNA damage repair genes through repressive chromatin modifications and is associated with DNA damage in prostate cancer cells. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Palomera-Sanchez Z, Watson GW, Wong CP, Beaver LM, Williams DE, Dashwood RH, Ho E |
Journal | J Nutr Biochem |
Volume | 47 |
Pagination | 113-119 |
Date Published | 2017 09 |
ISSN | 1873-4847 |
Keywords | Androgen Receptor Antagonists, Antineoplastic Agents, Phytogenic, Cell Line, Tumor, Chromatin, Chromatin Immunoprecipitation, DNA Damage, DNA Repair, DNA-Activated Protein Kinase, Enhancer of Zeste Homolog 2 Protein, Enzyme Repression, Epigenetic Repression, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Indoles, Male, MRE11 Homologue Protein, Neoplasm Proteins, Poly (ADP-Ribose) Polymerase-1, Prostatic Neoplasms, Receptors, Androgen, Response Elements |
Abstract | Androgen receptor (AR) is a transcription factor involved in normal prostate physiology and prostate cancer (PCa) development. 3,3'-Diindolylmethane (DIM) is a promising phytochemical agent against PCa that affects AR activity and epigenetic regulators in PCa cells. However, whether DIM suppresses PCa via epigenetic regulation of AR target genes is unknown. We assessed epigenetic regulation of AR target genes in LNCaP PCa cells and showed that DIM treatment led to epigenetic suppression of AR target genes involved in DNA repair (PARP1, MRE11, DNA-PK). Decreased expression of these genes was accompanied by an increase in repressive chromatin marks, loss of AR occupancy and EZH2 recruitment to their regulatory regions. Decreased DNA repair gene expression was associated with an increase in DNA damage (γH2Ax) and up-regulation of genomic repeat elements LINE1 and α-satellite. Our results suggest that DIM suppresses AR-dependent gene transcription through epigenetic modulation, leading to DNA damage and genome instability in PCa cells. |
DOI | 10.1016/j.jnutbio.2017.05.005 |
Alternate Journal | J. Nutr. Biochem. |
PubMed ID | 28582660 |
PubMed Central ID | PMC5583029 |
Grant List | P01 CA090890 / CA / NCI NIH HHS / United States P30 ES000210 / ES / NIEHS NIH HHS / United States |