Yin Yang 1 regulates the transcriptional activity of androgen receptor

Abstract

The multifunctional protein Yin Yang 1 (YY1) plays an important role in epigenetic regulation of gene expression. YY1 is highly expressed in various types of cancers, including prostate cancer. Currently, the mechanism underlying the functional role of YY1 in prostate tumorigenesis remains unclear. In this report, we investigated the functional interplay between YY1 and androgen receptor (AR), and the effect of YY1 on AR-mediated transcription. We found that YY1 physically interacts with AR both in a cell-free system and in cultured cells. YY1 is required for the optimal transcriptional activity of AR in promoting the transcription of the prostate specific antigen (PSA) promoter. However, ectopic YY1 expression in LNCaP cells did not further enhance the reporter driven by the PSA promoter, suggesting an optimal level of YY1 is already established in prostate tumor cells. Consistently, YY1 depletion in LNCaP cells reduced endogenous PSA levels, but overexpressed YY1 did not significantly increase PSA expression. We also observed that YY1-AR interaction is essential to YY1-mediated transcription activity of AR and YY1 is a necessary component in the complex binding to the androgen response element (ARE). Thus, our study demonstrates that YY1 interacts with AR and regulates its transcriptional activity.

Yin Yang 1

“…27 Our finding of YY1 as a coactivator of AR in promoting PSA transcription also implicates that YY1 potentially regulates prostate cancer development and progression through stimulating AR function. Especially, in the absence of androgen, we observed a modest activation by YY1 on AR-dependent transcription of the PSA promoter, 6 suggesting that, as a coactivator, overexpressed YY1 may be an essential regulator to the AR-signaling pathway in androgen independent prostate cancer.…”

“…Therefore, instead of directly acting as a transcription factor, YY1 plays a role of a cofactor and its DNA binding activity is dispensable in mediating PSA expression. It is noteworthy that AR interacts with the C-terminal of YY1, 6 where its DNA binding domain, the zinc finger region, is located. Therefore, it is unlikely that YY1 molecule can associate with its DNA binding element and AR protein concurrently.…”

“…Therefore, while a medium increase of YY1 stimulates AR-mediated transcription, further increases of YY1 can compromise this activation. 6 One possible reason for this phenomenon is that excessive YY1 associates with other coactivators to be recruited and therefore interferes with the transcriptional activation of a target gene, the so-called "squelching effect".…”

“…In our recent study, we observed YY1-dependent expression of prostatespecific antigen (PSA) in prostate cancer cells. 6 Due to the well-recognized function of YY1 as a transcription factor, we first tested whether YY1 directly regulates PSA transcription. When we mutated the only YY1 binding element in the PSA promoter, YY1-mediated transcription of PSA promoter was unaffected.…”

Yin Yang 1 (YY1) synergizes with Smad7 to inhibit TGF-β signaling in the nucleus

“…YY1 associates with androgen receptor (AR) and stimulates the expression of prostate-specific antigen (PSA) in prostate cancer cells, and a YY1 mutant deficient in DNA binding is similarly effective [33]; in addition, YY1 acts as a co-repressor for the transcription factor HOXA11, GON4L and ATF/CREB [3436]. Likewise, YY1 interacts with R-Smads (Smad1/2/3) and Smad4, inhibiting Smadmediated transcriptional responses by disrupting Smad-DNA binding, thus interfering with TGF-β/BMP-stimulated cell differentiation; all of these effects do not depend on the DNA binding activity of YY1 [37].…”