Yin Yang 1 (YY1) is a multifunctional protein and localized in both nuclei and cytoplasm. Nuclear YY1 can regulate gene transcription, but the activity of cytoplasmic YY1 is unclear. YY1 is overexpressed in many cancers and contributes to their aberrant gene expression through regulating both histone and nonhistone proteins. Reports from our group and others support a proliferative role of YY1 in breast cancer. In our preliminary studies, we revealed that increased YY1 expression correlates with poor prognoses in 258 breast cancer patients. We discovered a novel role of YY1 in promoting AKT activation through mTORC2 and this regulation is independent of PI3K-PIP3 signaling. We also found a positive correlation between YY1 expression and AKT phosphorylation at S473 in a breast cancer tissue microarray study. We mapped the AKT-binding site to the Oncoprotein Binding (OPB) domain of YY1. The peptide with the YY1 OPB sequence disrupted YY1-AKT interaction and inhibited breast cancer cell proliferation. Based on these data, we hypothesize that YY1-promoted AKT phosphorylation represents a novel mechanism of AKT activation. This process occurs through an AKT conformational change caused by YY1 binding and is independent of the AKT activation mediated by PI3K-PIP3 signaling. Our objective is to dissect the molecular mechanism underlying YY1-promoted AKT activation and determine whether YY1-regulated AKT activation is biologically important to the proliferative role of YY1 in breast cancer pathogenesis. We have two specific aims to test our hypotheses.
In Aim 1, we will determine the mechanisms of YY1-regulated AKT activation in breast cancer. In this aim, we will study whether YY1 binding alters the AKT conformation and whether YY1 promotes AKT's association with mTORC2.
In Aim 2, we will determine the biological importance of YY1-regulated AKT activation in breast cancer. In this aim, we will determine whether YY1-promoted AKT activation is essential to YY1's proliferative role in breast cells, and whether this novel activity of YY1 ca maintain AKT activation and cell proliferation when PI3K-PIP3 signaling is inhibited. The innovation of this proposal lies in its novel mechanism of AKT activation promoted by direct binding of YY1 without AKT-PIP3 association. This is also the first time to uncover an unrecognized activity of cytoplasmic YY1. Our study will advance the understanding of YY1-regulated cell proliferative network and reveal a novel regulatory protein contributing to the oncogenic signaling activities of AKT. It can also provide insights into determining new target points that can be treated combinatorially with PI3K inhibitors to improve the efficacies of breast cancer therapies.
YY1 is an important regulatory protein during oncogenesis, but the most essential signaling pathway by which YY1 regulates breast cancer pathogenesis remains unclear. Based on our preliminary data that revealed a novel function of YY1 in activating AKT independently of PI3K-PIP3 signaling, we will determine whether YY1 binding causes an AKT conformational change leading to its phosphorylation by mTORC2 and study the biological significance of YY1-promoted AKT activation in breast cancer. The achievement of this project will not only advance our understanding of AKT upstream regulation and YY1's regulatory mechanisms in breast cancer, but also provide insights into designing individualized therapies to treat breast cancer patients with overexpressed YY1 by simultaneously inhibiting both YY1 and PI3Ks.
|Cantrell, William; Huang, Yue; Menchaca, Antonio A et al. (2018) Synthesis and PI3 Kinase Inhibition Activity of a Wortmannin-Leucine Derivative. Molecules 23:|
|Wright, Emily W; Nelson Jr, Ronald A; Karpova, Yelena et al. (2018) Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines. Molecules 23:|
|Zhang, Qiang; Wan, Meimei; Shi, Jinming et al. (2016) Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation. J Mol Cell Biol 8:232-43|
|Kulik, George (2015) Personalized prostate cancer therapy based on systems analysis of the apoptosis regulatory network. Asian J Androl 17:471-4|
|Kulik, G (2014) Precision therapy to target apoptosis in prostate cancer. Exp Oncol 36:226-30|