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2.1. Overview of trithorax group activity in prostate cancer

It is now well established that TrxG counteracts PcG HPTMs to promote a transcriptionally competent chromatin state [34, 44]. An intricate regulatory network controls whether the repressive effect of PcG activity or the activating role of TrxG dominates at specific loci [45]. The best characterized interplay between these two families of epigenetic modifiers occurs during embryonic development. In undifferentiated cells, PcG is highly expressed and maintains lineage-specific genes in a transcriptionally incompetent state while TrxG activity is minimal [46]. In response to external differentiation cues, PcG activity is reduced while TrxG becomes functionally active. As a result, lineage-specific genes are expressed and drive the cell towards a differentiated state [46]. The classic example of TrxG and PcG interplay involves the regulation of the HOX locus(See Figure 1). First silenced by PcG in embryonic stem cells (ESCs), HOX genes are subsequently induced upon TrxG activation during differentiation [47].

The functional relationship between PcG and TrxG is not limited to development. Incorrect regulation of PcG and TrxG also plays an inherent role in cancer initiation and progression [48-51]. In cancer, many embryonic transcriptional programs are orchestrated and push tumor cells towards a more undifferentiated state [43]. This directly implicates PcG and TrxG as they regulate many common target tumor suppressor genes that inhibit differentiation, invasion, and cell cycle progression [41]. These tumor suppressor genes are turned off in cancer, correlating with increased PcG expression and H3K27 trimethylation [52]. This indicates that, in cancer cells, PcG somehow undergoes a gain of function while TrxG activity is lost at key metastasis-inhibitory loci. In this classical model, PcG therefore act as oncogenes while TrxG operate as tumor suppressors (See Figure 1).

Figure 1. Classical Model of the PcG-TrxG Interplay in Development and Cancer

However, this model does not explain all the data regarding TrxG in cancer as the expression of individual TrxG subunits is highly heterogeneous across, and within, different tumor types. According to the classical model, TrxG genes act as tumor suppressors and should therefore be consistently downregulated in malignant cells. In fact, the expression of some TrxG genes increases in cancerous tissues, suggesting an oncogenic role for these particular TrxG genes [52, 53]. This indicates that there must exist an additional level of complexity which regulates not only the expression of individual TrxG genes, but also the activity and sequence specificity of TrxG complexes. Since TrxG proteins function as multimeric structures, their activity is highly context-dependent [54]. Many factors need to be taken into consideration when trying to assess the molecular function of TrxG complexes in a given temporal and spatial context. First of all, what is the relative expression of the individual subunits present within the TrxG complex? If many subunits are overexpressed or underex-pressed, the composition of the complex changes, which might lead to functional differences. Second, which coregulators of these complexes are present? For example, a corepressor could bind to a given TrxG complex and inhibit its H3K4 methyltransferase ability. Another possibility is that a transcription factor expressed specifically in cancer cells binds to a TrxG complex and recruits it to a normally untargeted loci. Finally, how is TrxG activity regulated by PTMs of its individual subunits? Every TrxG complex is composed of multiple proteins, all of them able to be chemically modified at multiple residues. Each PTM potentially affects the activity of the complex and the additive effect of all these possible PTMs accounts for an astronomical number of possible transcriptional outcomes [21]. In summary, although the traditional model by which TrxG simply opposes PcG functions in cancer still represents a good approximation, it remains incomplete as additional factors regulate TrxG activity.

Even though the epigenetic landscape of PCa remains quite complex, interesting links can be found between histone modifiers and the metastatic process. PcG members EZH2 and BMI1 are both overexpressed in PCa and their elevated expression correlates with metastasis and poor prognosis [55-57]. Their importance in PCa progression is reflected by the numerous studies that explored the possibility of targeting them pharmacologically [58-61]. While the role of PcG has been extensively investigated, few studies directly assessed the role of TrxG in PCa. Our analysis revealed that although no individual TrxG genes shows consistently significant up- or downregulation, a very high proportion of metastatic prostate tumors contain at least one TrxG gene whose expression is deregulated. The accumulated evidence suggests that TrxG does not act only as traditional tumor suppressors which counteract PcG activity. In fact, individual TrxG genes can interact with other complexes to either promote or repress progression to metastasis. To account for this functional heterogeneity, we will review the current literature for individual TrxG gene previously associated with cancer and then discuss expression data from a publicly available PCa database. We will finish by proposing putative mechanisms of TrxG misregulation in PCa, with a focus on the metastatic process.

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