Abstract A25: Yin Yang 1 promotes AKT activation through direct protein binding

As a polycomb group protein, Yin Yang 1 (YY1) plays an important role in cancer epigenetics. YY1 regulates both gene expression and protein modifications, including histone acetylation and methylation. We recently reported a proliferative role of YY1 and its cytoplasmic presence in breast cancer. In the current study, we demonstrated that YY1 promotes AKT phosphorylation at S473, a marker of AKT activation. The immunostaining signal of YY1 and AKT(S473) phosphorylation positively correlated and colocalized in breast cancer tissues and cells. The oncogene protein binding (OPB) domain (G201-S226) of YY1 bound to AKT and was necessary for YY1 in promoting AKT phosphorylation. This novel function of YY1 is independent of its transcriptional activity because YY1 promoted AKT phosphorylation in an in vitro setting using purified proteins and YY1 mutants deficient in binding to DNA retained this activity. Our further studies revealed that YY1 interacted with the PH domain of AKT where PIP3 binds and its role in promoting AKT phosphorylation was abolished when we depleted mSIN1, a specific component of mTORC2 that mediates AKT(S473) phosphorylation. Thus, we discovered a PI3K-independent mechanism of mTORC2-mediated AKT activation stimulated by YY1 binding to its PH domain, which supports the proliferative role of YY1 in mammary oncogenesis. Citation Format: Qiang Zhang, Meimei Wan, David A. Horita, Lance D. Miller, Steven J. Kridel, Timothy E. Kute, George Kulik, Guangchao Sui. Yin Yang 1 promotes AKT activation through direct protein binding. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A25.