The Mediator complex acts as a crucial component in transcription regulation, in light of its ability to transduce signals from pathway-specific transcription factors (TFs) to regulate RNA polymerase II (RNAPII) activity [117,118]. Depending on its functional configuration, the Mediator complex consists of 25 to 30 proteins, which can be classified into four submodules—head, middle, tail and Mediator kinase (Cyclin-dependent kinase 8 (CDK8), 19) module. The CDK8 module contains CDK8 (or its CDK19 paralog), Cyclin C (encoded by CCNC), MED12 and MED13 subunits. CDK19, a highly conserved paralog of CDK8 in vertebrates, shares conservation in the kinase and cyclin binding domain but is divergent at the C-terminal tail [119]. CDK8 and CDK19 are incorporated into the Mediator kinase module by way of binding MED12 in a mutually exclusive manner. Cyclin-dependent kinase (CDK) proteins mainly consist of two types of members, cell cycle progression CDKs, such as CDK1, CDK2 and CDK4/6, and transcriptional CDKs, such as CDK7, CDK9 and CDK8/19 [120]. These transcriptional CDKs complex with their cyclin subunit to phosphorylate the C-terminal domain (CTD) of RNAPII, regulating transcription initiation, elongation and mRNA processing [121]. Unlike CDK7 and CDK9, CDK8/19 activity is dispensable for general transcription regulation and normal cell growth. Recently, the CDK8 kinase function has been linked to an “activation helix” placed by MED12 close to the CDK8 T-loop [122]. CDK8/19 acts downstream of several transcription factors, such as HIF-1α [123] and NFκB [124], to transcribe their target genes. In addition, apart from its action on RNAPII, CDK8 phosphorylates some TFs, such as SMAD, to regulate β/BMP signalling [125]. CDK8/19 is associated with diverse TFs to selectively enhance the expression of silent genes, implying their regulation is in a context-specific manner.

CDK8/19 has been implicated in several cancers, especially those induced by dysregulated gene expression rather than mutations [126]. It has been more than a decade since CDK8 was identified as an oncoprotein in colon cancer. CDK8 was found to act, in a kinase-dependent manner, as a driver of β-catenin-dependent transcription and colorectal cancer proliferation [127]. The underlying molecular mechanisms of how CDK8 regulates β-catenin-dependent transcription are less-well defined, especially considering that the critical kinase substrates of CDK8 that mediate this activity are yet to be identified. Converging genetic studies have demonstrated that the ability of CDK8 to drive β-catenin-regulated gene expression is likely Mediator complex dependent. Aside from CDK8, Mediator kinase submodule proteins MED12 and MED13 have been implicated in recruiting Mediator to Wnt-directed target genes and regulating β-catenin transcriptional output [128,129]. Furthermore, repressing the CDK8 co-factor, Cyclin C, produces similar influences on β-catenin-mediated transcription as the inhibition of CDK8 [127]. Nevertheless, it has also been proposed that CDK8 can exert its effects on β-catenin indirectly via potentially Mediator-independent mechanisms. Morris et al. suggested pRB and CDK8 can counteract the inhibition of E2F1 on β-catenin-regulated transcription to enhance the expression of Wnt/β-catenin genes [130]. Indeed, chromosomal copy number gains in both CDK8 and RB1 loci on 13q in colorectal cancer cells provide a clear explanation of how they select optimal conditions to antagonise E2F1 suppressions [127,130]. E2F1 can post-translationally degrade β-catenin [130] and can activate ICAT which disrupts β-catenin-TCF/LEF complex [131]. The physical interaction between CDK8 and E2F1 at the promoters of β-catenin targets, such as MYC, provides a basis for understanding how Mediator kinase may enhance β-catenin transcriptional output [130]. Subsequent studies have further demonstrated that CDK8 phosphorylates Ser375 on E2F1 in colon cancer cells. This phosphorylation alleviates the E2F1 repressive effects on β-catenin-associated transcription [132]. Together, these data imply that E2F1 could be one of the crucial substrates of CDK8 to enable its regulation on Wnt/β-catenin transcriptional output. Moreover, a recent study identifies YAP as a novel substrate of CDK8. In Hippo signalling, YAP is phosphorylated directly by CDK8 to induce its function, and the phosphorylated YAP can be regulated further by Zyxin, a zinc-binding phosphoprotein, to promote cell proliferation and migration in CRC [133]. In conclusion, CDK8 kinase activity plays an essential role in driving oncogenic events. It can activate different substrates that are associated with intestinal neoplasia and tumour progression. Accordingly, it is quite possible that therapeutic interventions targeting its kinase activity could have clinical value in the treatment of CRC.

Chromatin remodeling is an essential step for transcription regulation. The nucleosome, the basic subunit of chromatin, is composed of histones H2A, H2B, H3, H4 and 146 base pairs (bp) of DNA. These histone tails undergo diverse post-translational modifications, such as acetylation, methylation, phosphorylation, ubiquitination, sumoylation and ADP ribosylation. Such modifications can increase or decrease the accessibility of DNA for transcriptional regulators to coordinate gene expression [134,135,136]. Histone acetyltransferases (HATs) and deacetylases (HDACs) are associated with enhanced and decreased acetylation, which mark gene activation and repression, respectively [137]. Furthermore, histone methylation can both alter chromatin accessibility and epigenetically activate or inactivate gene expression. The dynamic balance between histone methylation and demethylation is mediated by histone methyltransferases (HMTs) and demethylases (HDMs), respectively [138]. In addition to histone modification, chromatin remodeling is also an important epigenetic event. ATP-dependent remodeling complexes can alter the location and configuration of the nucleosome, and the changed chromatin can participate in either gene activation or inhibition [137]. Epigenetic regulation is involved in various events, including transcription, replication, repair and genome stability. Lastly, chromatin modifiers have been reported to have essential influences on cancer etiology [139,140,141]. In Wnt signalling, various chromatin modifiers have been identified as activators or repressors of Wnt/β-catenin transcriptional outputs (Figure 5).