Future Challenges

The evidence points to there being multiple means by which polyamines can both positively and negatively influence the activity of histone acetylating and deacetylating enzymes. Such influence appears to lead to changes in the acetylation status of both histone and non-histone proteins. Fluctuating intracellular concentrations of polyamines do not result in global effects on histone acetylation and gene expression. Therefore, elucidation of the various regulatory mechanisms by which polyamines exert their influence on chromatin-modifying enzymes to modulate gene expression will probably best be accomplished by focusing within the context of individual polyamine-regulated genes. Moreover, it is now possible to individually evaluate the many known HAT and HDAC enzymes for their susceptibility to polyamines and to elucidate the direct or indirect action of polyamines on their function. It will be interesting to determine just how discriminating the polyamines are for the different classes of both HAT and HDAC enzymes. Use of modern molecular biology techniques facilitating the overexpression and isolation of the different protein acetylating enzymes should clarify whether overlapping specificities exist for histone and polyamine substrates; if so, the relevance for disease should be evaluated. Similarly, models featuring the overexpression of SSAT might be valuable for investigating the effects of competition between enzymes that acetylate proteins and those that acetylate polyamines for rate-limiting quantities of acetyl-CoA.

It has been postulated that normal histone acetylation, probably in conjunction with histone and DNA methylation, serves to imprint the appropriate chromosomal functional status on successive cell generations, thereby contributing to long-term regulation of gene expression (3,22,23). Progeny cells carry an imprint of the histone acetylation pattern present on parental chromosomes before cell division. In this way, acetylation status may act as a marker by which the state of gene activity is carried through from one cell generation to the next. Indeed, histone hyperacetylation has been implicated in the propagation of chromosomal structures during cell division over 80-100 generations (52). Thus, our finding that ODC overexpression can cause altered patterns of histone acetylation may have intriguing implications for ODC-promoted neoplastic growth. It is possible that heightened intracellular levels of polyamines could transiently cooperate with genetic defects to malignantly transform a cell, and then function to sustain the accompanying changes in histone acetylation that may serve to imprint the tumorigenic phenotype such that it is passed along through succeeding cell generations.

Experiments using ODC-overexpressing cell lines and transgenic mice have demonstrated for the first time that polyamines modulate enzymes that manage chromatin structure in mammalian cells and tissue. To date, relatively few chemical classes of inhibitors of histone deacetylases (i.e., sodium butyrate, Trichostatin A, Trapoxin, suberoylanilide hydroxamic acid), and even fewer nonprotein organic modulators of histone acetyltrans-ferases have been identified. Thus the finding that the naturally occurring polyamines can function to modulate HAT and HDAC enzymes is quite significant. Moreover, taken together, the results of studies reviewed here also define a specific mechanism by which aberrant polyamine biosynthesis may lead to inappropriate expression of genes involved in tumorigenesis. As such, this may have important implications for drug development. There is activity for developing inhibitors of histone deacetylases with the intent of promoting histone acetylation and inducing cell-cycle arrest or differentiation in transformed cells. Toward that same end, it is intriguing to consider the possibility of designing compounds that mimic the effect of polyamines in modulating HAT enzymes. On the other hand, these studies also raise a cautionary note with respect to the potential negative ramifications of inappropriate histone acetylation induced by drug treatment. Elucidation of the various ways in which polyamines influence chromatin-modifying enzymes and chromatin structure may provide some insight into the mechanism of action of some anticancer drugs in clinical trials, including some polyamine analogs. Thus, a better understanding of polyamine-mediated modulation of transcription-associated chromatin remodeling might greatly benefit future drug development efforts.

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