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Sulforaphane influences histone methylation in advanced prostate cancer cells (1045.15)
Author(s) -
Watson G,
Wickramasekara S,
PalomeraSanchez Z,
Black C,
Maier C,
Williams D,
Dashwood R,
Ho E
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1045.15
Subject(s) - ezh2 , chemistry , sulforaphane , histone methyltransferase , cancer research , methyltransferase , histone , histone h3 , histone deacetylase , prostate cancer , epigenetics , acetylation , cancer , methylation , biochemistry , biology , dna , genetics , gene
Sulforaphane (SFN) supplementation is well tolerated and exhibits cancer‐selective cytotoxicity in preclinical models. SFN decreases global DNA‐methyltransferase (DNMT) and histone deacetylase (HDAC) activity in prostate cancer (PCa) cells, two classes of chromatin modifying enzymes (CME) involved in heterochromatin (HC) establishment and stability. HC marks co‐occur due to coordinated CME activity; therefore, we hypothesized that deficiencies in DNMT and HDAC activity would lead to alterations in histone methyltransferase (HMT) activity. SFN (15 µM) led to a global decrease in histone H3 lysine 9 trimethylation (H3K9me3) in PC3 PCa cells. Investigation into the underlying mechanism suggests SFN influences the H3K9 HMT SUV39H1. SFN leads to SUV39H1 ubiquitination and acetylation, posttranslational marks that are associated with SUV39H1 instability and reduced enzymatic activity. SUV39H1 modification coincided with decreased HC stability. Inhibition of SUV39H1 activity by small molecule inhibitor is cytotoxic to PCa cells, suggesting SUV39H1 inactivation contributes to the cancer‐suppressive activity associated with SFN. Our results suggest that destabilization of HC plays an active role in mediating cytotoxicity in response to SFN and supports further development of SFN as a therapeutic option and SUV39H1 as a therapeutic target for PCa. Grant Funding Source : Supported by NIH P01 CA090890