Regulation of YY1 expression and activity

In addition to transcriptional regulation, YYl-mediated gene transcription and protein modifications, YY1 expression and function are also modulated at multiple levels.

4.1. YY1 is regulated by gene regulatory proteins

As a transcription factor, YY1 regulates the expression of itself through binding to consensus sequences in the first intron of the YY1 gene [82]. These YY1 binding sites are necessary for YY1 gene transcription. Interestingly, overexpressed exogenous YY1 inhibits the transcription of the endogenous YY1 gene, but the reduction of YY1 to normal levels restores this transcription, suggesting a negative feedback loop. Several other transcription factors regulate YY1 expression, including NF-kB, whose regulation of YY1 in prostate cancer will be discussed below.

Raf kinase inhibitor protein (RKIP) is a potential tumor suppressor gene based on its activity in suppressing metastasis and reduced expression in cancers. RKIP overexpression inhibits YY1 transcription and sensitizes cells to TRAIL-mediated apoptosis [83, 84].

In addition to transcription factors, other gene regulatory proteins also modulate YY1 expression. One example is G-quadruplex resolvase (G4R) 1 (also known as RHAU or DHX36], which upregulates YY1 expression by resolving secondary structures in the YY1 promoter. The G-quadruplex (G4) structure is a 4-stranded secondary DNA or RNA structure that is stabilized by non-canonical Hoogsteen hydrogen bonding of planar guanine quartets and their subsequent stacking [85]. G4 structures in gene promoters inhibit gene transcription, which can be relieved by G4 structure resolving helicases.

Both human and murine YY1 promoters have high contents of cytosine (C) and guanine (G) nucleotides that confer these promoters with the potential to form G4 structures [86, 87]. We recently demonstrated that the presence of G4 structures in the YY1 promoter inhibits YY1 expression [86]. High G/C content is a common feature of many proto-oncogenes, such as c-myc and Bcl-2, whereas the promoters of most tumor suppressor genes have reduced numbers of closely-linked guanosine runs [88]. The high G/C content of YY1 and the presence of G4 structures in its promoter and 5' UTR are strong indicators of the oncogenic nature of YY1.

4.2. YY1 is regulated by post-translational modifications

Lysine residues are one of the major targets of post-translational modifications, acting as a substrate for the addition of acetyl, methyl, ubiquitin or small ubiquitin modifier (SUMO) groups. YY1 contains 32 lysines, equivalent to 8% of its total amino acids, making YY1 a vulnerable target of multiple modifications. Of the 414 amino acids that compose YY1, all lysine residues are located within the 257 amino acids comprising the middle and C-terminal regions, but not in the first 157 residues (Figure 1).

YY1 recruits p300 and PCAF to mediate histone acetylation of target promoters. Meanwhile, both p300 and PCAF acetylate YY1 in the central region (residues 171-200), augmenting YY1-mediated gene repression [11]. PCAF also acetylates YY1 in the C-terminus and thereby interferes with YY1's ability to bind its DNA consensus sequence [11]. On the other hand, HDACs deacetylate YY1 residues in its central region but not at the C-terminus [11].

YY1 is modified by ubiquitin and SUMO groups. Treatment with a proteasome inhibitor led to an accumulation of YY1 protein, suggesting that YY1 degradation is likely regulated by ubiquitination [48]. However, YY1 mono-ubiquitination enhances its interaction with C-ter-minal binidng protein (CtBP) and HDAC3 to establish a repressive complex that inhibits the expression of matrix metalloprotease (MMP) -9, a protein promoting cell invasion [53].

PIASy, a SUMO-E3 ligase, promotes the conjugation of SUMO proteins to YY1. We reported that sumoylation exerts an inhibitory effect on YY1-mediated gene expression [89].

YY1 is also subject to other modifications that do not rely on lysine residues. Phosphorylation of YY1 at three particular sites modulates a number of YY1 activities [90]. Among them, serine 247 (Ser247) is located in the spacer region of YY1 while two other sites, threonines 348 and 378, are in YY1's DNA-binding domain (Figure 1). Phosphorylation of the two threonines, but not Ser247, abolishes the DNA binding ability of YY1. Threonine 39 of YY1 was recently identified to be phosphorylated by Polo-like kinase 1; however, its role in modulating YY1 activity remains undetermined [91].

Akt is a well-established oncogene and acts as a critical upstream signaling protein for cell proliferation and survival. YY1 was shown to interact with Akt and is likely a substrate of Akt-mediated phosphorylation. Specifically, YY1 phosphorylation decreased upon treatment with an inhibitor of phosphoinositide 3 kinase (PI3K) that mediates Akt activation [45].

4.3. YY1 is regulated by growth factors & other biomolecules

Oncogenesis involves the upregulation of multiple growth factors, some of which promote YY1 expression. Insulin-like growth factor-1 increases YY1 expression while its depletion significantly decreases YY1 levels [92-94]. Fibroblast growth factor (FGF) -2 also upregulates YY1 expression in vascular cells upon injury [95]. YY1 expression in prostate cancer cells is particularly sensitive to growth factors, which will be discussed below.

Other biomolecules, such as lipopolysaccharide and myeloid nuclear differentiation antigen (MNDA) can promote YY1 expression and modulate its activity through enhancing YY1-DNA association [18, 96]. Conversely, YY1 is negatively regulated by molecules that have anti-growth effects. For example, aphidicolin, the DNA synthesis inhibitor and apoptosis inducer, facilitiates YY1 translocation and cleavage [97, 98].

While YY1 negatively regulates miR-29, this miRNA also binds the 3' UTR of YY1 mRNA and inhibits its translation [59, 99]. The tumor suppressor miR-34a has also been shown to target YY1 and block its expression [100, 101].

Yin Yang (YY) 2 has 65% similarity to YY1 in the protein coding regions while their amino acid sequences share 56% similarity, which is mostly in their DNA binding regions [102]. Thus, YY2 binds the same consensus sequence as YY1, but with a much lower affinity [103]. Interestingly, YY2 exhibits opposing effects on shared YY1 transcriptional targets [104]. YY2 silencing reversed the antiproliferative effects of YY1 depletion [104]. Nonetheless, more studies are needed to delineate the mechanisms and interaction of YY1 and YY2.

Overall, YY1 is activated by different growth factors, whereas antiproliferative signals tend to antagonize YY1 activity. These data support an oncogenic role of YY1 in tumor development and progression.

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