Abstract 5436: Oct4 interaction with Hmgb2 regulates Akt signaling and the pluripotent gene expression signature.

Akt signaling impacts multiple cellular functions associated with the hallmark characteristics of pluripotency such as cell cycle progression, cell growth, and enhanced cellular survival. Constitutive Akt activation promotes the pluripotent state and has also been implicated in several forms of cancer. Recent studies have suggested that while Akt activation may be a positive factor, the active nuclear form of Akt is associated with poor prognosis for many cancers, including lung cancer. Here, we describe a novel transcriptional regulatory feedback loop between Oct4, Hmgb2, and Akt. We show that Akt signaling promotes Oct4 phosphorylation and stability. This maintains interaction with Akt, Hmbg2 and other members of the SET complex such as Nme1 and Set. Upon differentiation, when Akt is inactive, their decreased interaction is observed. A functional genomics approach was therefore employed to determine the relevance of Oct4 interaction with Hmgb2 in maintaining the pluripotent state. Despite its previously described role in Polycomb group recruitment and transcriptional repression in Drosophila, we find that Hmgb2 knockdown results in decreased Akt signaling and decreased expression of many Oct4 transcriptional targets including genes implicated in cell cycle regulation, DNA repair, chromatin structure, as well as the pluripotency regulators Oct4, Sox2, and Nanog. Taken together, our results suggest that Oct4, Hmgb2, and the SET complex participate in a PTM-dependent feed forward regulatory loop that promotes active Akt signaling and the pluripotent gene expression signature. Future work will be focused upon dissecting the role of this network in maintaining constitutive nuclear Akt activation and promoting the primitive epigenetic state found in cancer. These findings may provide insight into the role of Akt in lung cancer chemoresistance and suggest alternate targets for more efficacious treatment. Citation Format: Pearl A. Campbell, David J. Stewart, Michael A. Rudnicki. Oct4 interaction with Hmgb2 regulates Akt signaling and the pluripotent gene expression signature. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5436. doi:10.1158/1538-7445.AM2013-5436