Abstract 5253: PTEN represses oncogene expression by regulating Daxx-H3.3 deposition in the chromatin

Abstract

Abstract One of the most mutated and deleted gene in cancer is the tumor suppressor gene pten (phosphatase and tensin homology, deleted on chromosome ten). To further understand how PTEN inactivation contributes to cancer predisposition, we investigated how PTEN regulates gene expression. 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. We observed that PTEN regulates Histone 3.3 (H3.3 variant) loading in the chromatin by limiting Daxx interactions, and thereby controls expression of several tumor driver genes. Furthermore, when Daxx expression is disrupted in pten-deficient glioma stem cells, we observed a dramatic diminution of pluripotency transcription factors, a decrease in differentiation and sphere-forming capacity, and an increase in radiation sensitivity. In conclusion, this work supports a novel chromatin-associated function for PTEN that regulates H3.3 deposition, and gene expression, through Daxx interaction. This nominates Daxx as a therapeutic target to treat patients with gliomas and other types of cancers in which PTEN is mutated. Citation Format: Jorge A. Benitez, Webster K. Cavenee, Frank F. Furnari. PTEN represses oncogene expression by regulating Daxx-H3.3 deposition in the chromatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5253. doi:10.1158/1538-7445.AM2014-5253