Cruciferous vegetable intake is associated with reduced risk of
bladder cancer, yet mechanisms remain unclear. Cruciferous vegetable
isothiocyanates (ITCs), namely
sulforaphane (SFN) and
erucin (
ECN), significantly inhibit
histone deacetylase (HDAC) activity in human
bladder cancer cells representing superficial to invasive biology (59-83% inhibition with 20μM, 48h treatment), and in
bladder cancer xenografts (59±3%
ECN inhibition). Individual HDACs inhibited by SFN and
ECN include HDACs 1, 2, 4 and 6. Interestingly, global acetylation status of
histones H3 or H4 remain unaltered. The interplay between HDAC inhibition and modest modulation of AcH3 and AcH4 status is partially explained by decreased
histone acetyl
transferase activity (48.8±5.3%). In contrast, a significant decrease in phosphorylation status of all
isoforms of
histone H1 was observed, concomitant with increased
phosphatase PP1β and PP2A activity. Together, these findings suggest that ITCs modulate
histone status via HDAC inhibition and
phosphatase enhancement. This allows for reduced levels of
histone H1 phosphorylation, a marker correlated with human
bladder cancer progression. Therefore, ITC-mediated inhibition of
histone H1 phosphorylation presents a novel direction of research in elucidating epidemiological relationships and supports future food-based prevention strategies.
SIGNIFICANCE: Collectively, our findings suggest that the cruciferous vegetable
isothiocyanates:
sulforaphane (SFN) and
erucin (
ECN), impact
histones status in
bladder cancer cells by modulating specific HDACs and HATs, and enhancing
phosphatase activity, resulting in reduction of
histone H1 phosphorylation. These findings are significant due to the fact that our previous work positively correlated
histone H1 phosphorylation with
bladder cancer carcinogenesis and progression. Therefore, we propose that SFN and
ECN may inhibit bladder
carcinogenesis via epigenetic modulation of gene expression associated with
histone H1 phosphorylation. These efforts may elucidate
biomarkers useful in epidemiologic studies related to cruciferous vegetable intake and
cancer risk or provide intermediate
biomarkers for food-based clinical intervention studies in high-risk cohorts.