Abstract B05: The tumor suppressor gene pten regulates gene expression through histone H3.3 deposition and Daxx interaction

Abstract

Abstract Sustaining proliferation is one of many capabilities acquired during tumor progression, where the PI3-kinase signaling pathway is a positive regulator of this trait and the tumor suppressor gene PTEN (phosphatase and tensin homology, deleted on chromosome ten) a negative regulator. Since PTEN deregulation is a central component of cancer progression, we decided to investigate how PTEN post-translational modifications modulate its function and protein interactions. We found that the histone chaperon protein Daxx (death domain-associated protein) associates with PTEN, in vivo and in vitro, and regulates PTEN stability through acetylation and ubiquitination. Moreover, we observed that PTEN regulates Histone 3.3 (H3.3 variant) deposition in the chromatin, by limiting Daxx interactions. We found an elevated H3.3-Daxx association in pten null cells, compared with pten-wt cells, correlating with a low H3.3 enrichment in the promoter of some driver tumor genes (Fos, Myc, Cyclin D1 and Bcl2) and an increased gene expression of them. We further demonstrated that this indirect gene expression regulation by PTEN is independent of its lipid-phosphatase activity. In conclusion, we hypothesize that PTEN may be mediating its tumor suppression function in part by regulating H3.3 deposition, and gene expression, through Daxx interaction. Citation Format: Jorge A. Benitez, Webster K. Cavenee, Frank B. Furnari. The tumor suppressor gene pten regulates gene expression through histone H3.3 deposition and Daxx interaction. [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 B05.