Sulforaphane influences histone methylation in advanced prostate cancer cells (1045.15)
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abstract
Sulforaphane (SFN) supplementation is well tolerated and exhibits cancerselective cytotoxicity in preclinical models. SFN decreases global DNAmethyltransferase (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 cooccur 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 M) 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 cancersuppressive 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
