Conclusion

While for many years cancers were thought to arise as a result of genetic alterations, an increasing number of studies report that in fact epigenetic misregulation primarily drives PCa progression and metastasis [13, 128]. PcG proteins EZH2 and BMI1 are overexpressed in PCa, an event that correlates with increased metastatic spreading and poor prognosis [57]. Since TrxG antagonizes PcG action, we explored the possibility that aberrant TrxG signalling could also represent a key factor in PCa metastasis. Since PcG is overactive in PCa and TrxG counteracts PcG activity, TrxG were historically thought to be oncosuppressive [41]. Analysis of expression databases revealed that almost all metastatic prostate tumors show deregulated expression of at least one TrxG gene. Interestingly, an in-depth literature review combined with an analysis of expression data indicated that aberration in TrxG complexes impacts PCa progression in a way that goes beyond their anticipated roles as classical tumor suppressors. In fact, some TrxG genes show elevated expression in metastatic PCas and have been shown to interact with, and enhance the activity of, known oncogenes such as AR, c-MYC, h-RAS [68, 70]. The finding that TrxG genes can act as either oncogenes or tumor suppressors implies that the regulation of TrxG activity highly depends on the cellular context [68, 129]. Changes in individual TrxG gene expression, availability of coregulators, as well as post-translational modifications on both individual TrxG subunits and coregula-tors all regulate the functional output of TrxG complexes. These multiple levels of regulation account for the highly diversified spectrum of molecular processes affected by TrxG activity, and explain why some TrxG genes can act as oncogenes and others as tumor suppressors.

Since it is becoming increasingly clear that misregulated TrxG activity represents a key driver of PCa progression, an important question arises: How can TrxG complexes be targeted clinically? Inhibiting core TrxG subunits like MLL, ASH2L, and WDR5 does not represent a suitable strategy. TrxG complexes play many important physiological roles [130] and therefore disrupting these core TrxG proteins would result in high toxicity. In fact, it is important to recognize that TrxG activity is highly context-dependent and is controlled by many core-gulators. This context-dependency can be exploited in the search for new drug targets. An interesting strategy to adopt would be to identify TrxG coregulators that are overexpressed in PCa only. Inhibiting these coregulators would impair TrxG function in PCa cells specifically while leaving normal cells unaffected. Since TrxG complexes can be oncogenic or tumor suppressive, two types of coregulators should be targeted clinically. The first represents coactivators of oncogenic complexes and second, corepressors of oncosuppressive complexes. Pharmacologic disruption of both of these proteins would in theory limit the tumori-genic potential of aberrant TrxG signalling. To date, no such coregulators have been described in PCa. The link between TrxG and PCa remains poorly characterized and many more studies are required to understand the impact of dysregulated TrxG on PCa progression. Nonetheless, the implication of TrxG in PCa supports the idea that epigenetic alterations represent key drivers in the progression to metastatic disease.

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